Neutral results from a large cardiovascular outcomes trial of Sanofi's diabetes drug Lyxumia (lixisenatide) bode well not only for the glucagon-like peptide-1 receptor agonist's chances of finally reaching the U.S. market, but also for maintaining clinical confidence in the safety of the GLP-1 class.

Results from the 6,000-patient ELIXA CV outcomes trial, released June 8 at the American Diabetes Association's scientific sessions in Boston, showed that lixisenatide neither increased nor decreased the risk of major adverse cardiovascular events (MACE) compared to placebo in adults with type 2 diabetes and high CV risk (see chart below).

The ELIXA data may provide early clues as to what to expect from the ongoing and planned CV outcomes trials for other drugs in the GLP-1 class, some of which are not expected to report results for three or more years.

Meeting The Guidance Goalpost

On both the primary "MACE+" endpoint and FDA's preferred "MACE" endpoint, the upper bound of the 95% confidence interval fell below 1.3, thereby meeting the criteria established in FDA's December 2008 guidance on CV safety assessments for diabetes drugs Also see "FDA’s Diabetes Guidance On CV Risk Will Get First Test With Pending NDAs" - Pink Sheet, 22 December, 2008..

ELIXA Study Results
Cardiovascular Safety
Endpoint	Hazard Ratio (95% CI)
Major Adverse CV Events (MACE+) (comprising CV death, non-fatal myocardial infarction, non-fatal stroke, hospitalization for unstable angina)	1.017 (0.886, 1.168)
MACE (CV death, non-fatal MI, non-fatal stroke)	1.02 (0.887, 1.172)
Heart failure-related hospitalization	0.96 (0.75, 1.23)
Non-Cardiovascular Safety
Adverse Event	Lixisenatide vs. Placebo
Pancreatitis	0.2% vs. 0.3%
Pancreatic cancer	<0.1% vs.="">
Severe symptomatic hypoglycemia	0.3 vs. 0.6 events per 100 patient-years
Malignancy	2.9% vs. 2.6%
Drug-related allergic reactions	0.2% vs. 0.2%
Source: Sanofi press release

Also importantly, there was no increased risk of heart failure with lixisenatide.

Heart failure concerns have arisen in CV outcomes trials for some antidiabetic agents in the DPP-4 inhibitor class ([A#00150420014]).

However, data from the TECOS study of Merck & Co. Inc.'s DPP-4 inhibitor Januvia (sitagliptin), released the same day at ADA, showed no increased risk of heart failure (see related story,[A#14150608002]).

"People around the world are being treated with GLP-1 receptor agonists, and the CV effects were unknown," said Marc Pfeffer, a Harvard University cardiologist and chair of the ELIXA Steering Committee. "ELIXA goes beyond the FDA guidance to deliver data related to heart failure and other insights that are not currently available for any other GLP-1 receptor agonist."

In an interview with "The Pink Sheet" DAILY, Rachele Berria, VP and head of the diabetes medical unit for Sanofi US, said there were only "nice surprises" in the ELIXA results, including no increased risk of heart failure, pancreatitis, pancreatic cancer or hypoglycemia.

Peter Chang, principal scientific analyst at BioMedTracker, said the ELIXA data suggest lixisenatide is "very safe, and that was reassuring."

Late To Market, But First With CV Data

Even though lixisenatide is not yet approved in the U.S. and five other GLP-1 products are on the market, the ELIXA data are the first from a completed CV outcomes trial in this product class conducted pursuant to FDA's 2008 guidance.

Lixisenatide has been approved in Europe since 2013.

In September 2013, Sanofi withdraw the NDA following discussions with FDA about plans for reviewing interim data from ELIXA, opting instead to await the full results Also see "FDA CV Requirements Sideline Sanofi’s Lixisenatide" - Pink Sheet, 12 September, 2013..

"In hindsight, we're pleased and proud of that decision that was taken to fully complete this cardiovascular outcomes trial and have the full trial data available and reviewed in the scientific venue before we go ahead and file the product," Andrew Purcell, VP and head of the diabetes business unit at Sanofi US, said in an interview.

Now that it has the full data set in hand, Sanofi expects to resubmit the NDA in the third quarter ([A#14150319002]).

Sanofi officials declined to speculate on what labeling would look like. However, a label that reflects the ELIXA data could give lixisenatide a competitive leg-up in the crowded GLP-1 market where CV outcomes data are otherwise lacking – at least until data from the next completed outcomes trial are reported.

Novo Nordisk AS' 9,300-patient LEADER trial of Victoza (liraglutide) is scheduled to be completed in November, according to ClinicalTrials.gov.

EXSCEL, the 14,000-patient CV trial for AstraZeneca PLC's Bydureon (long-acting exenatide), is scheduled to be completed in 2018. Eli Lilly & Co.'s 9,600-patient REWIND trial of Trulicity (dulaglutide) and GlaxoSmithKline PLC's 9,400-patient trial of Tanzeum (albiglutide) are targeted for completion in 2019, according to ClincalTrials.gov.

The first GLP-1 receptor agonist on the U.S. market, AstraZeneca's Byetta (exenatide), was approved in 2005, more than three years before FDA began requiring dedicated CV safety assessments for type 2 diabetes drugs.

"Clearly the filing that we're putting together for resubmission to the FDA will be more robust than the original one because the full results of ELIXA will be included," Berria said.

However, BioMedTracker’s Chang questioned whether having the CV outcomes data in the label would really help lixisenatide gain traction against the other GLP-1 agents on the market.

"I'm not sure it's going to help them that much because I don't think people are going to expect the others are more dangerous," he said.

Sanofi's Lixisenatide Gets Clean Bill Of Health On CV Safety, Heart Failure

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