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FDA advisory committee rejects recommending approval of lower-dose empagliflozin for type 1 diabetes

The Endocrinologic and Metabolic Drugs Advisory Committee of the FDA voted 14-2 against recommending approval of a supplemental new drug application for the SGLT2 inhibitor empagliflozin 2.5 mg as an oral medication adjunct to insulin therapy for adults with type 1 diabetes, with committee members citing uncertainty regarding the adjudication of diabetic ketoacidosis 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, Boehringer Ingelheim) for type 2 diabetes. In briefing materials submitted to the FDA this week, Boehringer Ingelheim stated this proposed type 1 diabetes-specific dose of empagliflozin 2.5 mg offers efficacy comparable with the approved adjunct therapy pramlintide (Symlin, AstraZeneca), with a lower risk for diabetic ketoacidosis (DKA) when compared with higher doses.

Committee members, however, repeatedly noted that the evidence presented to support approval of a type 1 diabetes-specific dose of the drug raised questions regarding safety and efficacy, with findings based on a 26-week randomized controlled trial with 482 participants assigned either empagliflozin 2.5 mg or placebo.

“It is important to emphasize that we owe it to the patients with type 1 diabetes to do this right and provide sufficient evidence to know that we are offering them a benefit and to well characterize the risks, and I think doing a study with 241 patients [in each arm] probably doesn’t quite meet that bar,” Brendan M. Everett, MD, MPH, FACC, FAHA, assistant professor of medicine and director of general cardiology inpatient service at Brigham and Women’s Hospital and Harvard Medical School, said after his “no” vote.

“It is out of respect for them that I voted no,” Everett said.

Potential benefits ‘small’

Insulin and pramlintide are the only drugs currently approved for the treatment of type 1 diabetes in the United States. The advisory panel’s recommendations are nonbinding, although the FDA often follows its suggestions.

In its briefing materials, Boehringer Ingelheim noted it initially intended to register the two higher doses for type 1 diabetes, and the clinical development program was designed with this objective, investigating empagliflozin 10 mg and 25 mg in two phase 3 trials. The company additionally investigated the lower 2.5 mg dose based on an FDA recommendation in the EASE-3 trial.

 
The Endocrinologic and Metabolic Drugs Advisory Committee of the FDA voted 14-2 against recommending approval of a supplemental new drug application for the SGLT2 inhibitor empagliflozin 2.5 mg as an oral medication adjunct to insulin therapy for adults with type 1 diabetes.
Source: Adobe Stock

“The FDA noted ‘safety concerns specific to patients with type 1 diabetes that may warrant exploration of a lower dose,’” the company wrote in an executive summary. “The agency also highlighted that ‘we expect that the risk-benefit in this population will be different than in the type 2 diabetes population and are uncertain that doses approved for type 2 diabetes are optimal for type 1 diabetes.’”

The company stated that all three empagliflozin doses showed a positive risk-benefit profile; however, the 2.5 mg dose emerged with the most favorable profile for patients with type 1 diabetes, with a lower risk for DKA compared with the higher doses. The 2.5 mg dose yielded HbA1c reductions in the range of 0.3%, comparable to pramlintide, as well as a mean 1.8 kg reduction in body weight and a 2.1 mm Hg reduction in systolic blood pressure, with no increased risk for hypoglycemia.

However, in discussing the statistical efficacy of the drug, the FDA stated that the statistically significant 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. Additionally, the “numerically small benefit” in body weight reduction and systolic BP reduction did not rise to significance, and there was no benefit in reducing hypoglycemic events.

“These potential benefits for empagliflozin 2.5 mg from the EASE-3 trial are small in magnitude, and the average patient was in the non-hypertensive, non-obese range at baseline; hence, the clinical relevance is uncertain,” the FDA stated in briefing materials before the meeting.

Need for options

Kashif Munir, MD, associate professor of medicine and vice chief of the division of endocrinology, diabetes and nutrition at the University of Maryland School of Medicine in Baltimore, who voted in favor of recommending approval, said the findings were what he expected to see.

“I didn’t feel like this trial was a surprise, even though it was not as big as we wanted or as long as we wanted,” Munir said after the vote. “There is definitely a role for these medications. I use them myself for people with type 1 diabetes. Using a lower dose sacrificing some efficacy by helping with the safety end of things is a wise way to go.”

The FDA also stated that there was no imbalance in DKA events between participants treated with empagliflozin 2.5 mg and placebo, but the agency stressed the importance of assessing case severity.

“Some data suggest that DKA events in patients treated with SGLT2 inhibitors may have had a delayed diagnosis due to their atypical presentation (‘euglycemic’), which may have resulted in a more severe case by the time of diagnosis,” the agency wrote.

In a statement released shortly after the vote, Mohamed Eid, MD, MPH, MHA, vice president of clinical development and medical affairs, cardio-metabolism and respiratory medicine for Boehringer Ingelheim, said the meeting elevated the discussion regarding the challenges of managing blood glucose for those with type 1 diabetes and the need for new treatment options.

“We continue to believe the totality of data from the EASE program indicates a favorable benefit-risk profile for empagliflozin 2.5 mg as an adjunct to insulin in adults with type 1 diabetes and look forward to continuing to work with the FDA in this review process,” Eid said in the statement.

The FDA has been hesitant to accept SGLT inhibitor therapies in the United States for type 1 diabetes. In January, the committee voted 8-8 in a decision on whether to recommend approval of an NDA for oral sotagliflozin (Zynquista, Sanofi and Lexicon), a first-in-class dual SGLT1 and SGLT2 inhibitor for type 1 diabetes. At the time, several committee members expressed concerns about an observed risk in DKA and called for a risk evaluation and mitigation strategy if the therapy was approved. In March, the FDA rejected sotagliflozin. In July, the agency declined to expand the indication for another SGLT2 inhibitor, dapagliflozin (Farxiga, AstraZeneca), for use in type 1 diabetes. – by Regina Schaffer

References:

Boehringer Ingelheim briefing information. Available at: https://www.fda.gov/media/132424/download.

FDA briefing information. Available at: https://www.fda.gov/media/132422/download.

The Endocrinologic and Metabolic Drugs Advisory Committee of the FDA voted 14-2 against recommending approval of a supplemental new drug application for the SGLT2 inhibitor empagliflozin 2.5 mg as an oral medication adjunct to insulin therapy for adults with type 1 diabetes, with committee members citing uncertainty regarding the adjudication of diabetic ketoacidosis 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, Boehringer Ingelheim) for type 2 diabetes. In briefing materials submitted to the FDA this week, Boehringer Ingelheim stated this proposed type 1 diabetes-specific dose of empagliflozin 2.5 mg offers efficacy comparable with the approved adjunct therapy pramlintide (Symlin, AstraZeneca), with a lower risk for diabetic ketoacidosis (DKA) when compared with higher doses.

Committee members, however, repeatedly noted that the evidence presented to support approval of a type 1 diabetes-specific dose of the drug raised questions regarding safety and efficacy, with findings based on a 26-week randomized controlled trial with 482 participants assigned either empagliflozin 2.5 mg or placebo.

“It is important to emphasize that we owe it to the patients with type 1 diabetes to do this right and provide sufficient evidence to know that we are offering them a benefit and to well characterize the risks, and I think doing a study with 241 patients [in each arm] probably doesn’t quite meet that bar,” Brendan M. Everett, MD, MPH, FACC, FAHA, assistant professor of medicine and director of general cardiology inpatient service at Brigham and Women’s Hospital and Harvard Medical School, said after his “no” vote.

“It is out of respect for them that I voted no,” Everett said.

Potential benefits ‘small’

Insulin and pramlintide are the only drugs currently approved for the treatment of type 1 diabetes in the United States. The advisory panel’s recommendations are nonbinding, although the FDA often follows its suggestions.

In its briefing materials, Boehringer Ingelheim noted it initially intended to register the two higher doses for type 1 diabetes, and the clinical development program was designed with this objective, investigating empagliflozin 10 mg and 25 mg in two phase 3 trials. The company additionally investigated the lower 2.5 mg dose based on an FDA recommendation in the EASE-3 trial.

 
The Endocrinologic and Metabolic Drugs Advisory Committee of the FDA voted 14-2 against recommending approval of a supplemental new drug application for the SGLT2 inhibitor empagliflozin 2.5 mg as an oral medication adjunct to insulin therapy for adults with type 1 diabetes.
Source: Adobe Stock

“The FDA noted ‘safety concerns specific to patients with type 1 diabetes that may warrant exploration of a lower dose,’” the company wrote in an executive summary. “The agency also highlighted that ‘we expect that the risk-benefit in this population will be different than in the type 2 diabetes population and are uncertain that doses approved for type 2 diabetes are optimal for type 1 diabetes.’”

The company stated that all three empagliflozin doses showed a positive risk-benefit profile; however, the 2.5 mg dose emerged with the most favorable profile for patients with type 1 diabetes, with a lower risk for DKA compared with the higher doses. The 2.5 mg dose yielded HbA1c reductions in the range of 0.3%, comparable to pramlintide, as well as a mean 1.8 kg reduction in body weight and a 2.1 mm Hg reduction in systolic blood pressure, with no increased risk for hypoglycemia.

However, in discussing the statistical efficacy of the drug, the FDA stated that the statistically significant 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. Additionally, the “numerically small benefit” in body weight reduction and systolic BP reduction did not rise to significance, and there was no benefit in reducing hypoglycemic events.

“These potential benefits for empagliflozin 2.5 mg from the EASE-3 trial are small in magnitude, and the average patient was in the non-hypertensive, non-obese range at baseline; hence, the clinical relevance is uncertain,” the FDA stated in briefing materials before the meeting.

Need for options

Kashif Munir, MD, associate professor of medicine and vice chief of the division of endocrinology, diabetes and nutrition at the University of Maryland School of Medicine in Baltimore, who voted in favor of recommending approval, said the findings were what he expected to see.

“I didn’t feel like this trial was a surprise, even though it was not as big as we wanted or as long as we wanted,” Munir said after the vote. “There is definitely a role for these medications. I use them myself for people with type 1 diabetes. Using a lower dose sacrificing some efficacy by helping with the safety end of things is a wise way to go.”

The FDA also stated that there was no imbalance in DKA events between participants treated with empagliflozin 2.5 mg and placebo, but the agency stressed the importance of assessing case severity.

“Some data suggest that DKA events in patients treated with SGLT2 inhibitors may have had a delayed diagnosis due to their atypical presentation (‘euglycemic’), which may have resulted in a more severe case by the time of diagnosis,” the agency wrote.

In a statement released shortly after the vote, Mohamed Eid, MD, MPH, MHA, vice president of clinical development and medical affairs, cardio-metabolism and respiratory medicine for Boehringer Ingelheim, said the meeting elevated the discussion regarding the challenges of managing blood glucose for those with type 1 diabetes and the need for new treatment options.

“We continue to believe the totality of data from the EASE program indicates a favorable benefit-risk profile for empagliflozin 2.5 mg as an adjunct to insulin in adults with type 1 diabetes and look forward to continuing to work with the FDA in this review process,” Eid said in the statement.

The FDA has been hesitant to accept SGLT inhibitor therapies in the United States for type 1 diabetes. In January, the committee voted 8-8 in a decision on whether to recommend approval of an NDA for oral sotagliflozin (Zynquista, Sanofi and Lexicon), a first-in-class dual SGLT1 and SGLT2 inhibitor for type 1 diabetes. At the time, several committee members expressed concerns about an observed risk in DKA and called for a risk evaluation and mitigation strategy if the therapy was approved. In March, the FDA rejected sotagliflozin. In July, the agency declined to expand the indication for another SGLT2 inhibitor, dapagliflozin (Farxiga, AstraZeneca), for use in type 1 diabetes. – by Regina Schaffer

References:

Boehringer Ingelheim briefing information. Available at: https://www.fda.gov/media/132424/download.

FDA briefing information. Available at: https://www.fda.gov/media/132422/download.

    Perspective
    Satish K. Garg

    Satish K. Garg

    This decision represents a missed opportunity for patients with type 1 diabetes as there is a huge unmet need in this group. The application was based on a small study with 0.05% efficacy (with the drug arm), though the placebo-corrected efficacy was 0.25% (usually, in a 6-month study, one would expect maintenance of HbA1c at 6 months). Sotagliflozin or dapagliglozin could have been approvable except for the need for a better mitigation plan regarding DKA (especially with a prospective trial). Here, the efficacy is challengeable. That’s exactly what the committee’s decision came down to. Additionally, the study population was 97% white; you have no minority representation.

    The way DKA was classified in this study is questionable. For the sotagliflozin and dapagliflozin programs, every instance of DKA, acidosis and ketosis were called DKA.

    I know FDA wants to work in this space to help people with type 1 diabetes. The best chance was with sotagliflozin and dapagliflozin but for the DKA risk seen with those drugs. Empagliflozin has to be 10 mg and 25 mg or maybe 5 mg with a better DKA mitigation strategy. Now, there may be room for a 5 mg or 7.5 mg dose with a hope of getting 0.3% or 0.4% efficacy and mitigating the risk for DKA, and then you might have a chance for approval. I hope the companies will get together to plan for such a combined study, as there is really need for patients with type 1 diabetes.

    • Satish K. Garg, MD
    • Professor of Medicine and Pediatrics
      Barbara Davis Center for Diabetes
      University of Colorado Denver

    Disclosures: Garg reports he has served on advisory boards for Dexcom, Eli Lilly, Lexicon, Mannkind, Medtronic, Merck, Roche and Sanofi, and received research grants through his institution from Animas, Dario, Dexcom, Eli Lilly, JDRF, Lexicon, Medtronic, Merck, NIDDK, Novo Nordisk, Sanofi and T1D Exchange.