FDA rejects lower-dose empagliflozin 2.5 mg for type 1 diabetes
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The FDA on Friday issued a complete response letter for a supplemental new drug application for a 2.5 mg dose of the SGLT2 inhibitor empagliflozin as an adjunct to insulin for adults with type 1 diabetes, according to a press release from Boehringer Ingelheim and Eli Lilly.
The FDA issues a complete response letter to an applicant if the agency determines that it will not approve the application or abbreviated application in its present form for one or more reasons. As Healio previously reported, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 14-2 in November against recommending approval of a supplemental NDA for empagliflozin 2.5 mg as an oral medication adjunct to insulin therapy for adults with type 1 diabetes. Committee members cited uncertainty regarding the adjudication of diabetic ketoacidosis (DKA) and a lack of adequate data to support evidence for safety and efficacy.
The proposed dose is lower than currently approved 10 mg and 25 mg doses of empagliflozin (Jardiance) for type 2 diabetes.
“The challenges of managing blood sugar levels for those with type 1 diabetes, and the desire for new treatment options, reveal important unmet needs in the diabetes community,” Mohamed Eid, MD, MPH, MHA, vice president of clinical development and medical affairs, cardio-metabolism and respiratory medicine at Boehringer Ingelheim, said in the release. “We remain committed to the continued study of therapies that may improve outcomes for adults with cardiorenal metabolic conditions, including diabetes.”
Insulin and pramlintide (Symlin, AstraZeneca) are the only drugs currently approved for the treatment of type 1 diabetes in the United States, and other noninsulin therapies have met similar hurdles with the FDA. In March 2019, the FDA issued a complete response letter regarding an NDA for oral sotagliflozin (Zynquista, Sanofi and Lexicon), a first-in-class dual SGLT1 and SGLT2 inhibitor for adults with type 1 diabetes, also citing a potential increased risk for DKA. – by Regina Schaffer
Disclosure: Eid is vice president of clinical development and medical affairs, cardio-metabolism and respiratory medicine at Boehringer Ingelheim.
Perspective
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This decision was expected, as the FDA advisory committee voted 14-2 against recommending approval empagliflozin 2.5 mg for type 1 diabetes in November. The reason the advisory committee voted the way it did was because of the adjudication of diabetic ketoacidosis (DKA) and the lack of a demonstrated benefit/efficacy with this dose. The between-group HbA1c difference of –0.26% was attributable to a 0.2% HbA1c increase in the placebo group and a –0.05% decrease in the empagliflozin 2.5 mg group. If the lower dose provides so little benefit, then why bother? Why introduce possible adverse effects?
There were also issues with study design, which did not reflect the diversity of the overall U.S. population.
I do hope this is not the end of the road. Many of us are eager to continue to explore noninsulin therapies for type 1 diabetes, but there is a “pause” preventing any excitement in this area, for the reason that the FDA wants some sort of assurance that these people with type 1 diabetes are not going to die from DKA.
What I think may come out of this are new methods to noninvasively measure ketones. There are companies exploring this very idea and, in early studies, looking into continuous measurement of ketones that is similar to continuous glucose monitors. Of course, for ketones, frequency does not have to be every 5 minutes like with a CGM; this could be done once every 20 or 30 minutes. If this happens, and someone conducts a small study demonstrating you can mitigate the risk for DKA, the FDA may look at these drugs differently. For now — at least for the next year or two — I would not expect to see other noninsulin therapies for type 1 diabetes go before the FDA. Instead, SGLT2 inhibitors will continue to be used off-label in select patients with type 1 diabetes, who we ask to regularly monitor ketones.
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