FROM AN FDA ADVISORY COMMITTEE MEETING
In back-to back advisory committee hearings, the Food and Drug Administration received recommendations for approval of two new combination medications to treat type 2 diabetes. The two medications each combine long-lasting insulin with a glucagon-like peptide–1 (GLP-1) receptor agonist in a once-daily injectable fixed-dose combination.
On May 24, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) voted unanimously to approve the fixed-dose combination of liraglutide and insulin degludec (individually marketed as Victoza and Tresiba, respectively, by Novo Nordisk). The new combination was referred to as IDegLira in the sponsor’s clinical trials.
The following day, the EMDAC recommended in a 12-2 vote to approve Sanofi-Aventis’ new fixed-dose combination of lixisenatide and insulin glargine (Lantus), also indicated as an add-on to lifestyle management for type 2 diabetes. The sponsor’s proposed name for this combination is iGlarLixi.
For both products, most committee members felt that the combo would most benefit patients who were already on either insulin or a GLP-1 agonist (though the second day’s panel noted that data were lacking on patients transitioning from a GLP-1 agonist to Sanofi-Aventis’ lixisenatide/glargine combo). “I tend to agree with many of the people who have gone before me that the population of patients this should be used in are those that are on one of these two injectable medications already and in particular I think the GLP-1 agonist,” said Dr. Marie Gelato , professor of medicine at Stony Brook (N.Y.) University, who voted in favor of the liraglutide/degludec combination medication.
A concern common to discussion on both days was that some patients with diabetes and a higher body mass might not be able to benefit from these medications, since each one caps insulin dosing.
Other themes common to both days’ deliberations among the largely overlapping panels included the need for fine-tuning the dosing apparatus, labeling, patient interface, and nomenclature for these novel devices. For Dr. Robert Smith, panel chair and professor of endocrinology at Brown University, Providence, R.I., his vote on the second day should be “considered contingent on accomplishing those things adequately.”
Most of the endocrinologists on the committees noted that they personally felt more comfortable beginning a single agent, and probably tended to tinker with patients’ regimens fairly frequently at least during the initial period of diabetes management. However, the committees on both days felt that having the fixed-dose combination agent available might be a particularly useful tool for family practice physicians and those practicing general internal medicine.
Since the proposed lixisenatide/glargine combination would be dispensed as one of two pens, each with a different dose range of lixisenatide, the second day’s panel spent more time in discussion of the potential for confusion or misdosing with two choices.
“It’s incumbent upon the sponsor to make it easier for the doctor. I have confidence that they will work out the delivery system,” said Dr. Peter Wilson, explaining his rationale for voting for approval of the lixisenatide/glargine combo despite some reservations about the device and delivery system, “I think this will be a boon for the patients,” added Dr. Wilson, professor of medicine and public health at Emory University, Atlanta.
Lixisenatide, marketed as Lyxumia in Europe and elsewhere by Sanofi-Aventis, is pending FDA approval, so it received some additional attention during the committee hearing for lixisenatide/glargine. Though it would be the sixth GLP-1 agonist on the U.S. market, committee members did not voice concerns that it would be a “me too” drug; rather, said Dr. Wilson, “It provides yet another choice. … Choice is very important for physicians and for patients.”
During Sanofi-Aventis’ and the FDA’s presentations, safety data, especially as interpreted by the FDA, seemed to indicate a slightly elevated risk of significant allergic reactions with lixisenatide compared with placebo. However, conceded the FDA’s clinical reviewer Dr. Suchitra Balakrishnan, the postmarketing surveillance program for lixisenatide was “a larger program, which may have contributed to more events occurring.”
Earlier concerns about lixisenatide’s cardiovascular safety have been largely assuaged after publication late last year of results from the ELIXA trial ( N Engl J Med. 2015; 373:2247-57 ) that showed no increased risk – but no benefit – for those with type 2 diabetes taking lixisenatide.
The FDA usually follows the advice of its advisory committees.
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