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Two combination treatments for type 2 diabetes, along with another single agent, will come before an already skeptical FDA advisory committee this week.
A liraglutide (Victoza) and insulin degludec (Tresiba) combination from Novo Nordisk called IDegLira will be considered by the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) on Tuesday, followed by two drugs from Sanofi -- an insulin glargine (Lantus) and lixisenatide combo called iGlarLixi, and lixisenatide, which is a glucagon-like peptide-1 receptor (GLP-1) agonist, on Wednesday.
The FDA rejected Tresiba in 2013 before approving it in 2015. IDegLira has been approved in Europe under the name Xultophy.
IDegLira would be a once-daily, single injection combination of liraglutide and insulin degludec. The FDA has already conveyed concerns about the combo in a briefing document posted online ahead of Tuesday's hearing. The document states that because of "trial design concerns" the agency was not able to conclude that the combination would be better than insulin degludec alone.
While all phase III trials of IDegLira met their primary endpoints, and showed the superiority of IDegLira versus stand care, the brief outlines concerns over the specified starting dose and titration algorithm.
"Evaluations of the proportion of subjects who reached titration targets and the relative time needed to reach dose stabilization demonstrated that the titration algorithm resulted in a lag in both the proportion of subjects reaching glycemic targets and the time to reach dose stabilization in the comparator insulin arms of the trials, such that the HbA1c comparison between study arms was biased," the brief states.
Also, the HbA1c levels in a control group didn't "reflect a period of preceding glycemic stability."
There are no new concerns over the safety of IDegLira, but the agency noted that there are still some questions surrounding safety. Liraglutide could be taken in dosages that are lower than what has been approved in other phase III trials for glycemic lowering, and patients on the combination face the risks of both insulin and liraglutide.
The hearing will be streamed live online.
As for the Sanofi products, EMDAC will first consider lixisenatide, which proved in a trial last year to be safe, if not very effective, in treating diabetes, before turning its attention to iGlarLixi.
In briefing documents posted on Monday, the FDA indicated that they had reservations over the superiority of the combination drug, particularly since lixisenatide alone has not been shown to offer benefit at the low dosage it would be given as part of iGlarLixi.
Generally, lixisenatide is considered at a set dosage, but as part of a combination it is "transformed" into a titratable product, according to the agency.
"Interpreting the clinical meaningfulness of the results of a study designed to demonstrate 'contribution of the claimed effects' when one of the comparator is a titratable product is problematic," according to the brief.
Sanofi used a titrated dose of insulin to determine its contribution in iGlarLixi to establish that it was safe and effective. But when it came to determining lixisenatide's contribution, they used a titrated combination compared with insulin doses that were also titrated to a fasting glucose goal. In addition, few trials analyzed the drug at low doses, so the safety profile at that dosage is not clear.
Lixisenatide is available in Europe under the name Lyxumia.
Though the FDA is not required to follow the recommendations of its advisory committees, it usually does.