The FDA has published a briefing document ahead of the May 24 meeting of its Endocrinologic and Metabolic Drugs Advisory Committee to discuss the new drug application (NDA) for IDegLira (Novo Nordisk), a fixed-dose combination of insulin degludec (Tresiba) and liraglutide (Victoza). The product’s proposed indication is as an adjunct to diet and exercise to improve glycemic control in adults with type-2 diabetes mellitus.
FDA advisory committees are panels of independent experts who advise the FDA on specific questions raised by the FDA as they consider regulatory decisions. The FDA is not bound by the committee’s recommendation, but it takes its advice into consideration when reviewing an NDA.
IDegLira is a once-daily, single-injection combination product consisting of insulin degludec (Tresiba), a once-daily new-generation basal insulin analogue, and liraglutide (Victoza), a once-daily glucagon-like peptide-1 (GLP-1) analogue. Novo Nordisk submitted its NDA for IDegLira to the FDA in September 2015. The product was approved in 2014 in Europe, where it is marketed under the brand name Xultophy.
In a late-stage program, IDegLira was shown to be more effective than either insulin degludec or liraglutide alone in diabetes patients. But an internal assessment at the FDA has concluded that the trial design was biased in favor of the combination product, making it impossible for the FDA advisors to agree on the superiority of IDegLira compared with insulin degludec.
“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 FDA’s advisors observed. “Further, 26-week comparator HbA1c did not reflect a period of preceding glycemic stability. Due to these trial design concerns, we are not able to conclude that IDegLira is superior to IDeg [insulin degludec], as the applicant has concluded. To reach such a conclusion, a trial in which both arms were dosed and titrated in a maximally effective and balanced manner would be needed.”
With regard to practical utility, the advisors noted that patients currently treated with one of the two products in IDegLira can’t be easily switched to the combination product without a significant reduction in dose of the component they were previously receiving. For other marketed fixed-dose combinations, no dose reduction in either component is needed when making the switch.
Further, the available safety data indicate that patients taking IDegLira would be vulnerable to the adverse events associated with both of the components instead of just one.
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