FDA Rejects Empagliflozin for Type 2 Diabetes
Agency cites manufacturing deficiencies
The FDA has rejected the new drug application (NDA) for empagliflozin (Boehringer Ingelheim/Eli Lilly), an investigational sodium glucose co-transporter-2 (SGLT2) inhibitor.
The agency’s complete response letter (CRL) referenced previously observed deficiencies at a Boehringer Ingelheim facility where empagliflozin will be manufactured. The FDA stated that these deficiencies need to be resolved before the application can be approved. The FDA has not asked Boehringer Ingelheim to complete any new clinical trials to support the approval of the application.
Empagliflozin is being investigated for the reduction of blood glucose levels in adults with type 2 diabetes (T2D). The emerging SGLT2 inhibitor class removes excess glucose through the urine by blocking glucose re-absorption by the kidney.
The NDA for empagliflozin was based on results from one of the largest clinical registration programs in its class, involving more than 13,000 people with T2D.
In June 2013, Eli Lilly announced positive results from a pooled analysis of four pivotal phase III trials of empagliflozin in a total of 2,477 people with T2D.
In this analysis, presented at the American Diabetes Association 73rd Scientific Sessions, people with T2D treated with empagliflozin achieved significant reductions in hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), weight, and blood pressure compared with those given placebo after 24 weeks. In the same analysis, people treated with empagliflozin experienced an increased frequency of genital infections, but not urinary tract infections (UTIs), compared with people given placebo.
The placebo-adjusted efficacy results at 24 weeks for empagliflozin included:
- Reductions in HbA1c of 0.62% and 0.68% (P < 0.001) for 10 mg and 25 mg, respectively
- Decreases in FPG levels of 27.9 mg/dL and 30.6 mg/dL (P < 0.001) for 10 mg and 25 mg, respectively
- Loss of 3.99 lbs and 4.43 lbs (P < 0.001) in body weight for 10 mg and 25 mg, respectively
- Reductions in systolic blood pressure of 3.4 mm Hg and 3.8 mm Hg (P < 0.001) with 10 mg and 25 mg, respectively
- Reductions in diastolic blood pressure of 1.2 mm Hg and 1.5 mm Hg (P < 0.001) with 10 mg and 25 mg, respectively
- Reductions in uric acid of 0.50 mg/dL and 0.49 mg/dL (P < 0.001) with 10 mg and 25 mg, respectively, versus an increase of 0.02 mg/dL for placebo
Changes in lipid parameters were also observed:
- Low-density lipoprotein (LDL) cholesterol (“bad” cholesterol) increased (3.1 mg/dL for 10 mg [P = 0.060] and 3.9 mg/dL for 25 mg [P = 0.008]) versus an increase of 0.8 mg/dL for placebo
- High-density lipoprotein (HDL) cholesterol (“good” cholesterol) increased (2.7 mg/dL for both 10 mg and 25 mg; P < 0.001) versus no change for placebo
- Triglycerides decreased (9.7 mg/dL for 10 mg [P = 0.011] and 1.8 mg/dL for 25 mg [P = 0.321]) versus an increase of 2.7 mg/dL for placebo
The safety results with empagliflozin included:
- Incidence of UTIs comparable with that of placebo (9.3% and 7.5% for 10 mg and 25 mg, respectively, vs. 8.2% for placebo)
- Incidence of genital infections higher than that of placebo (4.2% and 3.6%t for 10 mg and 25 mg, respectively, vs. 0.7% for placebo)