As an FDA advisory committee prepares for a double header this week on two fixed-combination diabetes drugs, the agency seems to be balking a bit at the match-up of a basal insulin product that, when used alone, has a wide effective dose range with a glucagon-like peptide-1 (GLP-1) receptor agonist that has only one or two recommended effective doses.

The Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) will meet Tuesday to hear the pitch on Novo Nordisk A/S' combination comprised of insulin degludec (Tresiba) and liraglutide (Victoza). The next day, Sanofi SA will be at the mound with its combination of insulin glargine (Lantus) and lixisenatide, a GLP-1 product in-licensed from Zealand Pharma A/S. Both products are intended to help diabetes patients improve glycemic control, along with exercise and diet.

The products have thrown the FDA a curve ball, as all diabetes combo drugs the agency has approved to date pair either two fixed-dose products or two titratable products, with most of them coupling the widely used metformin with another oral anti-diabetic drug. Such combinations, whether they are fixed or titratable, can be used as a sequential add-on or as part of a dual therapy, the FDA said in its briefing documents for the EMDAC meetings.

A product combining one of each raises some clinical concerns, especially if a patient with type II diabetes hasn't tried either a basal insulin or a GLP-1 agonist. Although the FDA isn't calling the proposed combinations a no-hitter, it cited the same potential strikes against both products, noting the importance of an individualized, patient-centered approach in diabetes care.

Recognizing the different risks posed by insulin and GLP-1 agonists, the FDA wants EMDAC to coach it on whether the additional risks are justifiable when it's not known if the patient would get to the desired therapeutic goal with a single agent. If not, the agency wants to know who would most benefit from such a product.

Another strike is the loss of flexibility. The fixed combinations don't allow the two drugs to be dosed independently and limits how much insulin can be given. They also could result in a potentially ineffective dose of one of the agents in patients with low insulin requirements. And patients already on a GLP-1 agonist or insulin could have a reduction in their existing drug dose as they titrate up the fixed-ratio combo.

The combinations also could increase the potential for errors, the FDA said, due to their complex nature. For instance, the two active components aren't measured in the same terms: Insulin is measured in units and GLP-1 products are measured in milligrams or micrograms. The combination dose "is neither an accurate representation of an insulin unit nor an accurate representation of a weight-based measure term," the FDA said.

Unlike other insulin products, which can be titrated to meet the needs of the patient, the maximum dose for the combination is capped because of the GLP-1 component. If doctors are unaware of that, they could prescribe a GLP-1 overdose while trying to increase insulin levels.

After discussing the FDA's concerns, EMDAC will be asked to vote on whether each combo should be approved and then recommend postmarket studies.

CATCH-UP

While both Sanofi and Novo Nordisk will face the same questions, Sanofi has the added burden of pitching EMDAC on the clinical benefits of lixisenatide, which has a U.S. PDUFA date in July as a standalone diabetes therapy. The once-daily drug, marketed as Lyxumia, gained EU approval in 2013 and is now sold in more than 60 countries. Paris-based Sanofi delayed seeking U.S. approval for the drug until it completed a large cardiovascular outcomes trial (CVOT), which the FDA requires for all diabetes drugs. (See BioWorld Today, Sept. 13, 2013, and March 20, 2015.)

To play catch-up, Sanofi used a $245 million priority review voucher to speed the FDA's evaluation of its lixisenatide/Lantus (100 U/mL) combination, which it developed under a global licensing agreement with Zealand, of Copenhagen, Denmark. The voucher shaved four months off the review time, giving the combo product a PDUFA date in August.

Novo Nordisk, of Bagsvaerd, Denmark, has already launched its combo product in parts of Europe, where it's marketed as Xultophy. The EMA approved the combination in September 2014, but U.S. approval was delayed by the CVOT requirement for Tresiba, which is the long-acting insulin component of the combo. The FDA approved Tresiba Sept. 25.