Background Analysis: US FDA Advisory Committee to Review Proposed Expansion of Empagliflozin to Treat Type 1 Diabetes – NOV 13, 2019 (EMDAC)

Announcement

The US FDA has scheduled an Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) meeting for Wednesday, November 13, 2019 to discuss a supplemental new drug application (sNDA) for empagliflozin oral tablet, sponsored by Boehringer Ingelheim Pharmaceuticals, Inc. (BI), for use as an adjunct to insulin therapy to improve glycemic control in adults with type 1 diabetes mellitus (T1D).

Indication Background

T1D is characterized by an inability of the pancreas to produce insulin. As a result, people with the disease have to monitor their glucose levels throughout the day and accordingly, inject insulin to avoid becoming hyperglycemic.

Product Background

Empagliflozin inhibits a transporter that is involved in the reabsorption of glucose in the kidney, named sodium-glucose cotransporter type 2 (SGLT2). At oral daily doses of 10 and 25 mg daily, empagliflozin is approved (with US brand name Jardiance) as an adjunct to insulin for glycemic control in type 2 diabetes mellitus (T2D) patients, and also to reduce cardiovascular (CV) death in T2D patients with CV disease.

Products by Other Sponsors

Several SGLT2 inhibitors that are FDA-approved for T2D are undergoing evaluation for potential use in T1D, including: Sanofi-Aventis’ Zyquista (sotagliflozin); Pfizer’s Steglatro (ertugliflozin); Janssen’s Invokana (canagliflozin); and AstraZeneca’s Farxiga (dapagliflozin).

Clinical Trials of Proposed Indication

Top-line results of the two pivotal clinical trials, named EASE-2 (N = 710 T1D patients) and EASE-3 (N = 960 T1D patients), are presented below based on a press release made by BI on October 4, 2018. A comprehensive summary of the full data package submitted to the FDA, and detailed analyses by both BI and the FDA, will be made available 2 days prior to the EMDAC meeting, in briefing materials posted by the FDA. These materials will be summarized on the day they are posted, in our subsequent report, the Briefing Summary.

Regarding efficacy, BI reported that empagliflozin met the primary efficacy endpoint, defined as a change from baseline in HbA1c versus placebo after 26 weeks of treatment, for all doses investigated. The EASE-3 trial evaluated daily doses of 2.5, 10 and 25 mg as an adjunct to insulin over 26 weeks, and the EASE-2 trial evaluated daily doses of 10 and 25 mg as an adjunct to insulin over 52 weeks. In EASE-2, the placebo-corrected mean change from baseline in HbA1c at week 26 was -0.54% and -0.53% for empagliflozin 10 and 25 mg, respectively. In EASE-3, the placebo-corrected mean change from baseline in HbA1c at week 26 was -0.28%, -0.45% and -0.52% for empagliflozin 2.5 and 10 and 25 mg, respectively. BI says that, in addition to reductions in HbA1c, empagliflozin treatment was effective on secondary endpoints, showing reductions in weight, decreases in blood pressure, and decreases in total daily insulin dose. The company also says that data from continuous glucose monitoring indicated that patients treated with empagliflozin had improved glycemic variability and spent more time in range, although the press release acknowledges that data for the 2.5 mg dose are limited.

Regarding safety, BI reported that there was no increase in the risk of investigator-reported hypoglycemic events, including severe hypoglycemia, with empagliflozin treatment, which was a key secondary endpoint in the trials. Additionally, the company says patient-reported hypoglycemic events was reduced. The company also said the number of adjudicated diabetic ketoacidosis (DKA) events was comparable between empagliflozin 2.5 mg and placebo, and higher than placebo with empagliflozin 10 and 25 mg. Apart from incidence of DKA, BI says the safety profile was generally consistent with the previously reported safety profile of empagliflozin in adults with T2D.

In BI’s press release, Bernard Zinman, M.D., Professor in the Department of Medicine, University of Toronto and Senior Scientist at the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada, noted “Given the risk of DKA for people with type 1 diabetes, the 2.5 mg empagliflozin dose warrants consideration, as it balances glycemic and metabolic improvements that are relevant to patients without increasing their risk of DKA or other serious adverse events.”

Note: Trial results are posted online at ClinicalTrials.Gov, using the identifiers NCT02414958 and NCT02580591.

Regulatory Considerations

BI seeks to be the first sponsor to gain approval of an oral SGLT2 inhibitor to treat T1D. Several agents in the drug class have been FDA-approved to treat type 2 diabetes mellitus (T2D), but none have yet achieved an expanded indication for the treatment of T1D.

When the EMDAC met earlier this year to review an sNDA for a different SGLT inhibitor proposed to treat T1D (Sanofi-Aventis’ Zynquista (sotagliflozin)) the committee was split (8-8) over whether to recommend approval (EMDAC meeting dated January 17, 2019). The FDA’s briefing materials for sotagliflozin included a lengthy discussion about clinical endpoints for the development of antidiabetic drugs. The Agency explained that a reduction in HbA1c is considered a reliable biomarker for glycemic lowering and reduced onset and progression of microvascular complications, and is an accepted surrogate endpoint for regulatory decision-making for TD1M. The diabetes control and complications trial (DCCT) showed that there was a 43% reduction in microvascular risk for every 10% decrease in HbA1c. However, in regard to other glucose based endpoints in the sotagliflozin development program, including “glycemic variability” and “time-in-range,” the FDA said that these do not have an established relationship with long-term macrovascular and microvascular complications, and have not been validated for use in regulatory decision making for antidiabetic drugs. At the same time, the Agency acknowledged their value to patients and relation at least to short-term improvements in quality of life and treatment satisfaction. At the advisory committee meeting, the EMDAC debated the relevance of modest HbA1c reductions, and they generally felt that diabetes drug development programs should be enhanced by additional validated clinical outcome measures or biomarkers.

Some of the committee members who voted in favor of approving sotagliflozin felt that Risk Evaluation and Mitigation Strategies (REMS) could help to mitigate the primary risk of concern, DKA, such that benefit could outweigh the risk. Other committee members did not agree, leading to the split vote. Subsequently, the FDA issued a Complete Response Letter in response to the sotagliflozin sNDA.

For empagliflozin, it appears that BI may angle for approval of only the lowest dose of three doses that were evaluated, due to increased DKA that was seen with the two highest doses. However, BI’s regulatory strategy can only be confirmed once briefing materials post.

Regulatory Background

US Regulatory Background

unknown - PDUFA goal date (sNDA 204629/S-020)

What’s Next?

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: Boehringer Ingelheim Pharmaceuticals, Inc. Drug Name: empagliflozin Drug Class: sodium-glucose cotransporter type 2 inhibitor Indication: cardiovascular disease

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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.