Empagliflozin Likely Needs Another Trial After Rebuke By US FDA Panel

Expanded indication for type 1 diabetes seems out of reach for the moment, but if Boehringer conducts a larger and lengthier trial, it could eventually persuade members of the Endocrinologic and Metabolic Drugs Advisory Committee who voted 14-2 against supplemental approval of empagliflozin for the proposed 2.5mg dose.

Boehringer Ingelheim International GmbH will likely need to conduct another trial for empagliflozin after the US Food and Drug Administration's Endocrinologic and Metabolic Drugs Advisory Committee voted 14-2 that the benefits do not outweigh the risks as an adjunct to insulin to improve glycemic control in adults with type 1 diabetes mellitus.

Many panelists at the 13 November meeting said the existing data were promising, but they also felt that a larger trial of a longer duration is necessary to better characterize the risk of diabetic ketoacidosis (DKA) and the durability of benefit.

Boehringer is specifically seeking a supplemental approval for a distinct 2.5mg dose of empagliflozin for type 1 diabetes patients, which is smaller than the 10mg and 25mg doses recommended in its existing label for type 2 diabetes patients. The 2.5mg dose in type 1 diabetes would be marketed as a separate brand from Jardiance, which is the trade name for the type 2 diabetes dosage. 

Advisory Committee Vote

Do the available data suggest that the benefits outweigh the risks and support approval of empagliflozin 2.5 mg, administered orally once daily, as an adjunct to insulin to improve glycemic control in adults with type 1 diabetes mellitus? Y - 2, N - 14

In EASE-3, the single pivotal Phase III trial supporting approval, 2.5mg empagliflozin demonstrated a statistically significant -0.26% reduction of hemoglobin A1c (HbA1c) from baseline versus placebo over 26 weeks and also demonstrated modest benefits on weight and blood pressure.

However, only 241 patients received the 2.5mg dose of empagliflozin; the FDA recommended the company explore a lower dose for type 1 diabetes patients because of a different risk/benefit profile expected in this population. The agency questioned in its briefing documents whether the sample size and 26-week length of the trial were adequate to assess the safety and efficacy. (Also see "Boehringer's Empagliflozin Heads To Advisory Cmte. With Questions On Treatment Effect" - Pink Sheet, 11 Nov, 2019.)

The panel shared these concerns. 

"I remain optimistic that the regimen will ultimately prove to be useful," said Erica Brittain, a mathematical statistician at the National Institute of Allergy and Infectious Diseases. "There wasn't anything very worrisome about the results of the study, but just that one six-month study was insufficient to assess the tradeoff between benefit and risk."

Duke University Medical Center professor Thomas Weber added that, "I do feel the data are promising and would recommend a more robust assessment of efficacy and safety."

A sodium-glucose co-transporter 2 (SGLT2) inhibitor, empagliflozin is currently indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus and to reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and established cardiovascular disease.

Mohamed Eid, vice president, Clinical Development & Medical Affairs, Cardio-Metabolism & Respiratory Medicine at Boehringer, said in a statement following the meeting, "We continue to believe the totality of data from the EASE 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."

Characterizing The DKA Risk

Several panelists laid out specifics about how they would like to see the potential DKA risk studied when explaining their votes. SGLT2 inhibitors are known to increase the risk of DKA, which occurs due to insulin deficiency.

UT Southwestern Medical Center professor James de Lemos said that a future trial would need to include "several thousand individuals."

"I think that the next study that needs to be done has to focus on safety with regard to DKA, and it has to be large enough to do that. ... We need a trial large enough to get a precise signal about DKA rates," de Lemos said.

Other panelists called for expanding the definition of positively adjudicated DKA cases. In EASE-3, DKA events were classified as "certain," "potential," "unlikely ketoacidosis but ketosis," or "unlikely." Only two patients receiving 2.5mg empagliflozin had DKA events labeled as "certain" compared with three placebo recipients, although the FDA and the advisory committee raised concerns that DKA rates may be higher in the real world without the intense monitoring that takes place during clinical trials.

Michael Blaha, a professor at the Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, called for a study that focuses exclusively on the DKA safety issue.

"The primary outcome here would be, let's call it broad DKA," Blaha said. "We have to think carefully about what that means. But it would be a safety study."

Blaha also cited a few reasons why such a trial would be beneficial.

"I guess from the company's point of view its certainly worth the investment," he said. But also for the biology. Understanding this disease, it would be extremely worth the investment. It would teach us a lot about type 1 diabetes, DKA. It would teach us a lot about SGLT2 inhibitors, but also just the concept of adding on therapies for insulin reduction in type 1 diabetes, where these seems to be a large gap in knowledge."

Advisory committee members also recommended that the trial test Boehringer's risk mitigation proposals, such as educational materials about ketone monitoring.

In terms of length, Weber recommended Boehringer conduct a clinical trial of at least two years in length that is "adequately powered and adequate to establish efficacy in HbA1c, and also gather adequate patient-year exposure to more definitively and acceptably characterize the risk of diabetic ketoacidosis."

Connie Newman, a professor at the NYU Langone School of Medicine suggested a randomized controlled trial of at least one year "with a consideration to including microvascular outcomes, and also consideration to extending the trial beyond one year, perhaps in an open-label fashion so we get more data about safety."

Results Aren't Durable

Many panelists also felt that they couldn't make conclusions about the durability of the HbA1c reduction results for 2.5mg empagliflozin with just 26 weeks of data to look at.

"I think we need a larger, longer randomized controlled trial on the 2.5mg dose," said Cecilia Low Wang, a professor at the University of Colorado Anschutz Medical Campus School of Medicine. "I think we do have some evidence that that is the dose. But I think we need to see reproducibility, durability of the benefits both on A1c reduction, possibly other benefits as well, maybe decreased microvascular complications."

Newman offered a similar assessment.

"I feel that this database on the dose of 2.5mg is too small and in too short of a time period to even know what the efficacy in terms of glycemic control may be," she said. "The purported reduction of 0.26 may not actually be clinically meaningful, in my opinion, and that may not be what would happen in year 1 or year 2."

The 'Yes' Voters

Anna McCollister, founder of VitalCrowd and the panel's consumer representative, was among the small minority supporting approval. Her "yes" vote came in spite of her calling the patient sample size in EASE-3 "borderline insulting."

On the DKA risk, McCollister, herself a diabetes patient, commented that, "I think that DKA is a big risk as a clinical issue, but I don't know that this drug introduces that much of a greater risk in the relative scheme of things."

McCollister added that the DKA risk is one that can be mitigated through education and conversations with physicians.

What's more, McCollister noted that SGLT2 inhibitors are being used off-label and contended that an approval for empagliflozin would make its use in clinical practice less risky.

"From my perspective as a patient/consumer, I think the real question that we need to consider is whether we want people to take this class of medications without knowing what's happening and without having any rigorous requirements on the part of manufacturers to track it," McCollister said. "I think I would rather have that happen in a regulated environment where there is a degree of responsibility."

But de Lemos pushed back against such an approach.

"This concept of approving a drug so that we can monitor its use when we don't know it's safe and effective seems like an incredibly slippery slope," he said. "Absolutely no would be my answer to that. Our role and the agency's role is to make sure the package that's submitted provides evidence that the risk/benefit is favorable. If we don't have that, putting it on the market so we can learn more about it in a regulated way doesn't seem like the right way to go. "

The other vote in favor of approval came from University of Maryland School of Medicine professor Kashif Munir.

"I think at the end of the day, I agree it would have been nice to see more data and a longer trial, but I feel like the data were what I expected them to be," Munir said. "I felt the DKA risk would be there, it's real, but that it would be less than the higher doses. And I felt like the efficacy would be less than the higher doses. And that's exactly what we saw."

[Editor's note: This story has been updated to note that the 2.5mg dose of empagliflozin in type 1 diabetes would be marketed under a different brand name than Jardiance. A previous version of this story referred to the type 1 diabetes dosage also as Jardiance.]