The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) gave qualified support Wednesday for Sanofi SA’s fixed-ratio combination diabetes product, voting 12-2 to recommend approval. (One panelist had to leave before the vote.)

While the panelists agreed that the insulin glargine (Lantus)/lixisenatide combo demonstrated safety and efficacy in type 2 diabetes, several expressed concerns about the Solostar pen devices used to deliver the once-daily injection. Those concerns resulted in the no votes and a number of qualified yes votes.

The Paris-based drug company has proposed making the combo available via two Solostar pen devices. One would inject the drugs on a 2:1 ratio with an insulin range of 10-40 units/mL, with the second one providing a 3:1 ratio with an insulin range of 30-60 units/mL.

Xultophy, a similar combination by Bagsvaerd, Denmark-based Novo Nordisk A/S, which EMDAC unanimously supported Tuesday, would be available in only one pen, with a cap of 50 units/mL of insulin. While Sanofi’s two pens would provide more flexibility, they also could lead to medication errors. The FDA noted that in a small human factors trial, a pharmacist chose the wrong pen. (See BioWorld Today, May 25, 2016.)

Michael Reed, director of the Rainbow Clinical Research Center at the University Hospitals Case Medical Center, voted for approval of the Sanofi combo, saying the basal insulin/glucagon-like peptide-1 (GLP-1) receptor agonist product “may have the opportunity to change the paradigm” of diabetes treatment. But he added, “I struggle tremendously with the device.”

Ellen Seely, professor of medicine at Harvard Medical School, agreed. “The pen needs to be redesigned,” she said.

Kenneth Burman, director of the integrated endocrine training program at Medstar Georgetown University Hospital, cited the trial errors with the pen device as the reason for his no vote. However, he said Sanofi and the FDA should be able to work those problems out.

The panelists had no issue with having two different pens, but they want more differentiation. Color was a big issue. While the pens are different colors, several panelists worried that the difference might not be apparent to people who are colorblind or to elderly patients with vision problems.

Summarizing the panelists’ views about the pen, EMDAC Chairman Robert Smith, an endocrinology professor at Brown University’s Alpert School of Medicine, said no one was objecting to the construct of the pens, but they were concerned about how they were labeled, colored and structured.

If the agency agrees that the current pen design is a problem, the question is whether it can be resolved by the product’s August PDUFA date. In its race to market against Novo Nordisk, Sanofi cashed in a $245 million priority review voucher to cut four months from the FDA review time of its combo.


Another concern is how to educate all the people who might have to interface with a novel insulin/GLP-1 combination – whether it’s the Sanofi or Novo product. Sanofi is planning a comprehensive education campaign for health care providers and will include live support for patients. But panelist Steven Meisel, system director of patient safety at Fairview Health Services, questioned how the sponsor could effectively educate 5 million doctors, nurses, pharmacists and others who might have to interact with patients using the combo.

The committee members reiterated a labeling concern they raised Tuesday when they considered Xultophy, a once-daily, single injection that combines insulin degludec (Tresiba) and liraglutide (Victoza). They again urged the FDA to come up with a standardized vocabulary for measuring the doses, especially since insulin is measured in units and GLP-1 agonists are measured in micrograms. If the numbers on the dial-a-dose injector pens correspond with insulin units, the fear is that patients and health care providers will see the combos as another insulin product and ignore the GLP-1 component.

“This apparently is the wave of the future,” patient representative Barbara Berney said of the combo drugs. Thus, the FDA needs to quickly figure out how to measure such products, she told agency staff.

Sanofi had a tougher row to hoe this week than Novo Nordisk as it also had to convince EMDAC of the merits of lixisenatide, which has yet to be approved by the FDA. The GLP-1 agonist, in-licensed from Zealand Pharma A/S, has a July PDUFA date. However, it’s already been approved in more than 60 countries, including Japan and the EU, where it’s marketed as Lyxumia. (See BioWorld Today, May 24, 2016.)

In presenting lixisenatide and the fixed-ratio combo, Sanofi stressed that the GLP-1’s ability to reduce postprandial glucose levels complements the insulin action on fasting levels. And the drug’s apparent ability to counter the weight gains associated with insulin was seen as a real selling point for patients.

Although the committee didn’t vote on approval of lixisenatide as a standalone drug, the members were asked to discuss issues related to its efficacy and safety. While they stressed the need for monitoring for allergic reactions, the panelists welcomed the drug as another advance in the field.

Getting to market is just the first step. Should both combos be approved, Novo’s Xultophy could have an edge as patients and doctors already are familiar with liraglutide, which was approved in the U.S. as Victoza in 2010.

Since 2012, Victoza has been the most oft-dispensed GLP-1 at outpatient retail pharmacies in the U.S., according to data the FDA presented Tuesday. Prescriptions have scaled up every year it’s been on the market. In the 12 months ended March 31, 2015, nearly 600,000 patients picked up Victoza at U.S. pharmacies. (See BioWorld Today, Jan. 27, 2010.)

If approved, the combo products also could compete with regimens using once-daily insulin injections with a weekly GLP-1 injection such as Bydureon (exenatide, Amylin Pharmaceuticals Inc./Eli Lilly and Co.). Bydureon was the second most frequently dispensed GLP-1 agonist at U.S. retail pharmacies, with prescriptions dispensed for about 200,000 patients in the 12 months ended March 31, 2015.