A Food and Drug Administration advisory panel voted 14-2 against recommending approval of a supplemental New Drug Application for empagliflozin () as an adjunct to insulin therapy to improve glycemic control in adults with type 1 diabetes. The drug is already is approved for people with type 2 diabetes.
Members of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee cited persisting concerns about the risk for diabetic ketoacidosis (DKA) seen with the drug, as well as the limited pool of evidence Boehringer Ingelheim presented. Patients with type 1 diabetes are at increased risk for DKA.
The agency said it typically gets two major studies to support applications for drug approvals, but the application reviewed Nov. 13 rested largely on a single phase 3 trial, in which 241 people with type 1 diabetes took a low dose (2.5 mg) of empagliflozin for about 6 months. Panelists repeatedly objected to the paucity of data they had to consider this expanded approval.
“We owe it to patients with type 1 diabetes to do this right,” saidof Harvard Medical School, Boston, who served as a panelist. “It’s out of respect for them that I voted no.”
Boehringer Ingelheim, and members of the public argued that people with type 1 diabetes want access to new medicines such as empagliflozin that already are available for people with type 2 diabetes. The agency approved the drug in 2014 at doses of 10 mg and 25 mg as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. In 2016, it approved a new indication for empagliflozin for reducing risk of cardiovascular death in people with type 2 disease.
The panelists said they were sympathetic to that point of view, but stressed the need for further larger studies of empagliflozin in people with type 1 diabetes.
“I do think this is promising,” said panelist, of Johns Hopkins University, Baltimore. “But I’m not sure we are here to evaluate promising things. We’re here to evaluate proven things.”
The FDA advisers also said there was a need for greater clarity about reporting of adverse events in testing of this drug. The FDA reviewers reported disagreements with Boehringer about some cases classified as “unlikely ketoacidosis but ketosis” in the study.
“Some events adjudicated as ‘unlikely ketoacidosis but ketosis’ were clinically significant serious events requiring hospitalizations and prompt intervention, such as discontinuation of study drug,” wrote Mahtab Niyyati, MD, an FDA clinical reviewer, in her slides for the meeting.
The FDA is not obliged to accept the suggestions of its advisory panels, but it often does.
The agency did not ask the panel to weigh in directly on whether to approve the drug. Instead, the question put to the panel for a vote was whether the available data suggest that the benefits outweigh the risks of empagliflozin and support approval of a 2.5-mg dose as an adjunct to insulin for people with type 1 diabetes.
Empagliflozin is part of the sodium-glucose cotransporter 2 (SGLT2) inhibitor class of medicines, already known to have a risk for DKA, the agency noted in its briefing document for the meeting. DKA occurs as a result of insulin deficiency and subsequent ketogenesis.
There are no SGLT2 inhibitors approved for type 1 diabetes, the staff said in the review. The agency has rebuffed recent bids by makers of other SGLT2 drugs for people with type 1 diabetes. In July, AstraZeneca said the FDA had not approved its application for use of dapagliflozin () as an adjunct treatment to insulin to improve glycemic control in adult patients with type1 diabetes, when insulin alone does not provide adequate glycemic control. AstraZeneca said it was working with the agency on issues raised in the response letter it received.
In March, the FDA blocked a bid by Sanofi for approval of its investigational SGLT1/2 inhibitor, sotagliflozin (Zynquista) for use in people with type 1 diabetes. A panel had voted 8-8 in January on a question about the additional approval for this drug.
At the Nov. 13 meeting, panel members offered comments about the potential design of a new test for empagliflozin in type 1 diabetes, including a suggestion for a 2-year trial.
, the consumer representative on the FDA panel, cast one of the two votes in favor of use of the drug for people with type 1 diabetes. She said the agency needed to press for more research in this field but also argued that patients can manage the risks of treatments they find valuable. She cited, as an example, how she has stuck with an insulin pump to manage her own type 1 diabetes, despite having setbacks with the device that sent her to the emergency department.
The other vote in support of the empagliflozin application came from panelistmedical director of the University of Maryland Center for Diabetes and Endrocrinology, Baltimore. In explaining his vote, Dr. Munir noted that he and other physicians already are prescribing medications such as empagliflozin for people with type 1 diabetes, even though it is an off-label use. Boehringer’s strategy of using a lower dose of the drug for this group of patients would mean a reduction in effectiveness but also would lower the risk for side effects.
“Some of us do use existing medications” and have patients take partial doses, Dr. Munir said, adding that the current off-label use of the drug persuaded him to vote in favor of expanded approval, despite his concerns about the data.
Empagliflozin given at 2.5 mg resulted in a statistically significant difference of 0.26% in change in hemoglobin HbA1c at week 26, compared with placebo, said Roberto Crackel, PhD, an FDA mathematical statistician, during the presentation. There was a numerically small benefit in body weight and systolic blood pressure, but no benefit in reducing hypoglycemic events, he said.
In concluding, the agency’s presentation, Dr. Niyyati presented a slide depicting potential risk and benefit for empagliflozin with 6 months and then 6.5 years of follow-up. It showed that in terms of the benefit of HbA1c control, there is a potential but undemonstrated reduction in the risk of microvascular complications at 6 months and an estimated 2.8% reduction in microvascular complications after 6.5 years.
In terms of risk of DKA, there are limited data with unstable estimates, ranging to perhaps as many as 468 additional patients-with-events per 10,000 patients at the 6-month point. By the 6.5-year mark, treating 10,000 patients could result in 1,494 additional events.
In a statement issued after the panel’s vote, Boehringer and its partner on empagliflozin, Eli Lilly, stressed the benefit seen with the drug, a statistically significant reduction in HbA1c (0.28%), compared with insulin given with a matched placebo in adults with type 1 diabetes. Secondary endpoints of the trial demonstrated reductions in weight (1.8 kg) and systolic blood pressure (2.1 mm Hg), compared with insulin plus placebo, the companies said.
“We continue to believe the totality of data from the[Empagliflozin as Adjunctive to Insulin Therapy] program indicates a favorable benefit-risk profile for empagliflozin 2.5 mg in adults with type 1 diabetes and look forward to continuing to work with the FDA in this review process,” said vice president, clinical development & medical affairs, cardiometabolism & respiratory medicine, Boehringer Ingelheim, in a statement.
Speaking as a member of the public,, founder of the diaTribe Foundation, urged the FDA to “think creatively” about approval of the drug.” Many people already are using empagliflozin off label, she said. An FDA approval would help physicians and their patients manage the risks of this medicine. Without such help, patients may be needlessly exposed to harm, she argued.
“That’s what happens with popular unregulated drugs that payers cover, and we know that many, many payers are covering this drug for people with type 1,” she said.
, founder and senior adviser to Public Citizen’s health research group, made the opposing argument during the public session. The trial, in which 241 took the low dose of the drug and 241 on placebo, was “underpowered” in Dr. Wolfe’s view. He also stressed the issue that the FDA had raised about adjudication of the cases of side effects.
An FDA approval of the 2.5-mg dose would send “a dangerous false green signal to those doctors who are already prescribing off-label” drugs in SGLT2 inhibitor class, he said.
That would foster a misleading perception “that we have found the sweet spot” balancing safety and risk, he added. “I can’t see how the FDA or the advisory committee would suggest approval” of empagliflozin for type 1 diabetes.”