Sanofi's fixed-ratio combination of Lantus (insulin glargine) and the GLP-1 agonist lixisenatide got a passing grade from FDA's external advisors May 25, but the company may need to redesign the dosing device before the product can reach market.

The sponsor also faces the prospects of post-marketing studies on use of the combination product by patients experienced with GLP-1 agonists and the risk of allergic reactions with the combination's lixisenatide component.

In a 12-2 vote, the Endocrinologic and Metabolic Drugs Advisory Committee recommended approval of the combination product, known as iGlarLixi, for treatment of adults with type 2 diabetes.

"I feel really strongly that you cannot use the proposed pen, that the pen really needs to be redesigned," panelist Seely said.

It was the committee's second endorsement of an insulin/GLP-1 agonist combination in two days; on May 24, the panel voted unanimously in support of approval of Novo Nordisk AS' iDegLira, which combines Tresiba (insulin degludec) and Victoza (liraglutide) ([A#14160524004]).

Panelists generally said the Sanofi combination made sense from a mechanistic level, was effective in reducing HbA1c levels and would provide prescribers and patients with another option for managing type 2 diabetes. However, they expressed strong reservations about the design, color and labeling of the proposed dosing device.

Sanofi has proposed to market iGlarLixi in disposable pen injectors at two different dosage strengths. The formulations would be differentiated by pen color (yellow and green) and recommended dosing range of insulin units (10-40 units and 30-60 units) ([A#14160523001]).

'Delivering Something That Is Not Insulin As If It's Insulin'

Many committee members saw the potential for medication errors and confusion due to the product's labeling according to insulin units, problems in differentiating the two pen colors and ability to administer less-than-recommended doses.

In voting for approval, Ellen Seely, an endocrinologist at Brigham and Women's Hospital, said combining the two antidiabetic agents into one preparation that can be given as single injection would be helpful. However, "I feel really strongly that you cannot use the proposed pen, that the pen really needs to be redesigned," she said.

Seely and other panelists took particular issue with the pen's proposed labeling based on units of insulin dosed, without mention of the amount of lixisenatide that is also administered. The GLP-1 agonist is dosed in micrograms.

"You cannot be delivering something that is not insulin as if it's insulin in units," she said. "I think that is really asking for trouble."

Michael Reed, director of the Rainbow Clinical Research Center at Rainbow Babies and Children's Hospital in Cleveland, said he voted to approve the combination because it potentially could change the treatment paradigm for type 2 diabetes.

"I struggled tremendously with the device," Reed said, noting concerns raised by other panelists about the ability of patients with vision problems or color blindness to select the right pen.

"I don't really have a problem with two different devices," Reed said. "I feel concerned about the confusion in dosing and how it may be confused" in dispensing.

Reed said he also had "major concerns" about labeling the product according to units of insulin dosed. "I appeal to the FDA … this isn't the first, it's not the last, we've got to come up with some kind of naming convention or some kind of standardized way of labeling the dose."

"We're not objecting to the notion of this construct altogether in this pen," panel chairman Robert Smith, an endocrinologist at Brown University, said in summarizing the panel's discussion on issues specific to the product presentation and device. "But we're saying … that there is really a challenge here in terms of how to adequately label it, color it, structure it and then educate the people who are going to be using this or going to interface with it one way or another."

Dearth Of Data On GLP-1-Experienced Patients

Sanofi has positioned iGlarLixi as appropriate for patients needing glucose-lowering intensification beyond oral antidiabetic agents and basal insulin.

The company conducted two Phase III studies in type 2 diabetics naïve to insulin or GLP-1 receptor agonists, and in patients on basal insulin requiring additional glycemic control. The studies demonstrated iGlarLixi to be statistically superior to lixisenatide or insulin glargine alone in HbA1c reduction.

However, FDA clinical reviewer Suchitra Balakrishnan said the agency has concerns about this superiority claim due to study design issues, include the titration algorithm used. In addition, the insulin dose was capped at 60 units per day, whereas in clinical practice insulin dose can be increased without a limit. This raises questions as to whether the study results are clinically generalizable, she said.

Panelists generally did not view these concerns as a barrier to approval. However, they were disappointed that Sanofi has not studied use of the combination in patients on GLP-1 agonists who required additional glycemic control.

Paul Chew, Sanofi's senior VP-R&D, said the company is about to start a trial in patients who are switched from GLP-1 agonists to the combination.

Committee members generally said the most appropriate patients for the combination product were those experienced on basal insulin or GLP-1 agonists. However, they acknowledged the dearth of data for this latter group, and said FDA should require a post-marketing study in this population.

"All of us want to see some further information especially on taking insulin or a GLP-1 agonist and then adding the combination," said Peter Wilson, a cardiologist and endocrinologist at Emory University. "I think that's where endocrinologists especially will want to see more science as we move forward."

Panelists also said FDA should require post-approval monitoring for allergic reactions, including hypersensitivity and anaphylaxis, with the combination product and single-agent. FDA's review of lixisenatide, which is approved outside the US, identified a potential increased risk of serious hypersensitivity reactions compared to other GLP-1 agonists.

Although the advisory committee meeting reflected the agency's review of the separate NDAs for lixisenatide and iGlarLixi, FDA did not ask for an approval vote on the single-agent product. The user fee date for lixisenatide is July 27.

The combination product is undergoing a priority review, thanks to a voucher that Sanofi purchased for $245m. The user fee goal date is in August.

Lantus/Lixisenatide Combo Gets FDA Panel Nod, But Not Sanofi's Device

More from United States

More from North America