Although longtime leaders in diabetes therapies,Sanofi and Eli Lilly & Co.are both latecomers to the emerging battleground of glucagon-like peptide-1 agonists. With their compounds now in Phase III, however, the companies are providing glimpses, albeit limited, of their differentiation strategies in an increasingly crowded field Also see "Insulin The Focus At ADA 2012, But Don’t Forget GLP-1s And SGLT-2s" - Pink Sheet, 7 June, 2012..

GLP-1s are used once patients are no longer getting the benefits of oral treatments, before they begin insulin. The first GLP-1 – Amylin Pharmaceuticals Inc.’s twice-daily Byetta (exenatide) – hit the market in 2005. Longer-acting formulations have since joined Byetta: Novo Nordisk AS’s once-daily Victoza (liraglutide), which was approved in February 2010, and Amylin’s Bydureon, a once-weekly version of Byetta, which FDA cleared in January. The entry of two new competitors lowered Byetta’s share of the market to 30% from 44%, but increased the size of the market overall by 63% Also see "Riding High, Victoza Hopes To Gain Ground Over Popular DPP-4s With Label Change" - Pink Sheet, 16 April, 2012.. The GLP-1 market was worth about $1.7 billion in 2011, or about 6% of the worldwide market for diabetes drugs.

In an April 3 note, Jefferies & Co. Inc. analyst Peter Welford estimated the market for once-daily GLP-1s in 2018 will amount to $4 billion and that once-weeklies could “catapult the market” to $6 billion.

GlaxoSmithKline Inc. is set to file for approval of its Phase III GLP-1 albiglutide by the end of 2012 Also see "GSK Airs Phase III Data For Weekly GLP-1 Albiglutide, Plans To File By Year-End" - Pink Sheet, 3 April, 2012.. Roche and Ipsen were previously developing a GLP-1 called taspoglutide, but chose not to move forward with the compound after safety problems surfaced Also see "Roche/Ipsen's Suspended Taspoglutide Could Become Another Diabetes Casualty" - Pink Sheet, 10 September, 2010..

The American Diabetes Association(ADA) annual meeting, held from June 8 through 13 in Philadelphia, highlighted existing options and emerging competitors.

Dulaglutide Shows No CV Signals

At an investors’ forum on June 11, held in conjunction with the ADA meeting, Lilly reiterated the data from its mid-stage study of its GLP-1, dulaglutide. While it had previously released the results in May at the 2012 American Society of Hypertension meeting, it used the investor spotlight to highlight the drug’s hypertension benefits, implying that these have the potential to be a differentiator.

The Phase II study, which enrolled 755 type 2 diabetics, was designed with a primary endpoint comparing dulaglutide’s effect on blood pressure and heart rate to placebo. The drug, given in two doses during the 16-week trial, 0.75 mg and 1.5 mg, was found at the lower dose to be non-inferior to placebo in its effect on the mean systolic blood pressure over a 24-hour period and superior at the higher dose. Secondary endpoints showed the drug to be non-inferior at both doses for diastolic blood pressure, as compared to placebo, and non-inferior at the lower dose to improved heart rate. At the higher dose, the drug did not demonstrate a meaningfully better effect on heart rate.

It was, Lilly says, the first large, randomized trial to look at the effects of a GLP-1 on blood pressure and heart rate using ambulatory blood pressure monitoring, a gold standard. The ABPM is a non-invasive automated measure of an individual’s blood pressure over time—in this case, every 15 to 30 minutes over 24 hours. Lilly executives did not elaborate on the benefits of using ABPM as a measurement tool, so speculating on how the trial design as compared to those evaluating other drugs will be received by clinicians is difficult.

Diabetes drug makers are required to show that their drugs do not increase a range of cardiovascular risks, but few, if any, have included hypertension as a primary endpoint in their clinical trial packages, or used ABPM to measure it.

“We know that from studies investigating other GLP-1 analogs that they have reported small reductions in systolic blood pressure as well as small increases in heart rate. However, these findings are based on clinic measures done as safety assessments in these trials, not [as a] primary endpoint,” said Mary Jane Geiger, a senior medical advisory at Lilly. “In addition, we know that there is a need for us to thoroughly assess the cardiac risk of our ongoing and newly developing diabetes therapies.”

The study also showed that a 1.5 mg dose of dulaglutide reduced fasting blood glucose levels. Patients experienced a 2.5 kg (5.5 pounds) weight loss on average, which is typical for this class of drugs.

The company is currently conducting five Phase III studies dubbed AWARD 1-5. Four of these studies are expected to report out later this year, and data from the final study will be available in early 2013. Dulaglutide is expected to be filed for approval with FDA at about that time. As required by FDA, the company is also conducting a large, cardiovascular outcomes study, which is ongoing. Lilly is also expecting results from AWARD 6 and 7; AWARD 6 compares dulaglutide to Novo’s Victoza, and AWARD 7 will look at the effects of the drug in patients with chronic kidney disease.

Sanofi Prepares Lixisenatide For Filing

Meanwhile, Sanofi is planning to file its once-daily GLP-1, Lyxumia (lixisenatide), for approval with FDA by the fourth quarter of this year. It has already filed for approval in the EU and Japan.

“In addition to a significant lowering of fasting glycemia, there is a very pronounced lowering of postprandial glycemia,” Riccaro Perfetti, the VP Medical Affairs of Global Diabetes for Sanofi, told investors on June 12. “There is a very interesting and favorable safety profile with a low risk for hypoglycemia.”

The company conducted three of its late-stage studies of lixisenatide, which is partnered with Zealand Pharma AS, in combination with basal insulin; Sanofi has plans to roll out a combination therapy of lixisenatide with its blockbuster basal insulin Lantus (insulin glargine) if its gains approval for the GLP-1 on its own. This, it believes, will give the drug a leg up over other drugs in the market and allow it to take market share from the already strong Victoza brand.

“Lyxumia/Lantus combo is likely to have clinical relevance (trials to start in 2013); however success may largely rest on the attributes of the device (the ability to titrate the insulin dose may find favour),” wrote UBS analyst Gbola Amusa in a June 11 note.

The company also conducted a proof-of-concept study that lasted only 28 days and tested the drug against competitor Victoza. “On day 28, the group treated with lixisenatide was able to abolish the excursion in blood glucose, and they were stable throughout the challenge, but people exposed to liraglutide had only a marginal reduction of blood glucose in response to the challenge,” said Perfetti.

Diabetes Leaders Lilly, Sanofi Give A Glimpse Of GLP-1 Strategy

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