Merck and Pfizer’s ertugliflozin meets primary endpoints in two type 2 diabetes studies

In the studies, both doses of ertugliflozin tested (5 mg and 15 mg daily) achieved statistically significant reductions in A1C, a measure of average blood glucose over a two- to three-month timeframe, when added to metformin or in initial co-administration with sitagliptin.

The results of these studies, along with 52-week extension data from three other studies in the VERTIS clinical development program of ertugliflozin, will be presented at the 77th Scientific Sessions of the American Diabetes Association (ADA) in San Diego.

“We are pleased to share these new Phase 3 data with the scientific community that support the product profile of ertugliflozin as add-on therapy to metformin or for first-line use when combined with sitagliptin,” said Sam Engel, M.D., associate vice president, Merck clinical research, cardiometabolic and women’s health. “These studies are important milestones on our journey to bring this medicine to adults with type 2 diabetes and the physicians who care for them.”

“These results, combined with findings from other studies in the VERTIS program, underscore the potential of ertugliflozin as an important therapeutic option for adults with type 2 diabetes to help improve their glycemic control,” said James Rusnak, M.D., Ph.D., chief development officer, cardiovascular and metabolic diseases, Pfizer Global Product Development.

“As the global burden of diabetes continues to rise, we are committed to meeting patients’ needs with additional treatment options to help manage their condition.”

VERTIS MET, a 26-week study, evaluated the efficacy and safety of ertugliflozin in combination with metformin, compared with placebo and metformin, in adults with type 2 diabetes uncontrolled on metformin monotherapy. The study showed patients taking ertugliflozin 5 mg or 15 mg and metformin experienced greater reductions in A1C compared to placebo (0.7 percent and 0.9 percent, respectively, compared with 0.0 percent for placebo, p<0.001, for both comparisons).

Ertugliflozin in combination with metformin also met a secondary endpoint in the study, as significantly more patients taking either ertugliflozin 5 mg or 15 mg achieved the ADA’s recommended A1C treatment goal of less than 7.0 percent compared with placebo and metformin.

As add-on therapy to metformin, treatment with ertugliflozin also resulted in significant reductions in fasting plasma glucose (FPG), body weight, systolic blood pressure (SBP) and diastolic blood pressure (DBP), compared with placebo.

The 26-week VERTIS SITA study compared the efficacy and safety of initial combination therapy with ertugliflozin and Merck’s DPP-4 inhibitor JANUVIA® (sitagliptin) with placebo. In this study, patients taking ertugliflozin 5 mg or 15 mg, in combination with sitagliptin 100 mg, experienced greater reductions in A1C compared with patients taking placebo alone (1.6 percent and 1.7 percent, respectively, compared with 0.4 percent in patients taking placebo, p<0.001 for both comparisons).

Additionally, the co-administration of ertugliflozin and sitagliptin met a secondary endpoint in the study, as significantly more patients taking ertugliflozin 5 mg or 15 mg, in combination with sitagliptin 100 mg, achieved the A1C treatment goal of less than 7.0 percent.

Treatment with the initial combination of ertugliflozin and sitagliptin also resulted in significant reductions in FPG, body weight and SBP, compared with placebo.

Ertugliflozin is being investigated in the VERTIS clinical development program, which is comprised of nine Phase 3 trials in approximately 12,600 adults with type 2 diabetes. VERTIS CV, the ongoing cardiovascular (CV) outcomes trial of ertugliflozin, recently completed enrollment with approximately 8,000 patients.

The primary endpoint of VERTIS CV is to assess the non-inferiority of ertugliflozin to placebo on the composite of CV death, nonfatal myocardial infarction or nonfatal stroke (MACE). In 2016, the trial was expanded and pre-specified secondary endpoints were added to test for superiority on the composite of CV death and hospitalization for heart failure, and for superiority on CV death alone.

Marketing applications for ertugliflozin and for two fixed-dose combination products (ertugliflozin and JANUVIA, ertugliflozin and metformin) are under review with the U.S. Food & Drug Administration (FDA) and the European Medicines Agency. The Prescription Drug User Fee Act (PDUFA) action date from the FDA is in December 2017 for the three New Drug Applications.

Results from VERTIS MET: Ertugliflozin When Added to Metformin Therapy (1168-P)

In this randomized, double-blind 26-week investigational multicenter study, 621 patients with type 2 diabetes and a baseline A1C of 7.0 – 10.5 percent, who were inadequately controlled with metformin monotherapy (greater or equal to 1,500 mg/day for more than or equal to 8 weeks), were randomized to receive placebo, ertugliflozin 5 mg/day or ertugliflozin 15 mg/day in a 1:1:1 ratio, as an add-on therapy to metformin.

In addition to meeting the study’s primary endpoint of improved blood glucose control at 26 weeks, ertugliflozin in combination with metformin also met a key secondary endpoint in the study, as significantly more patients taking ertugliflozin 5 mg and 15 mg in combination with metformin achieved the ADA’s recommended A1C treatment goal of less than 7.0 percent (35.3 percent and 40.0 percent, respectively) compared with placebo and metformin (15.8 percent) (p<0.001, for both comparisons based on adjusted odds ratio comparisons).

The following statistically significant placebo-adjusted reductions were observed for the primary and additional key secondary endpoints for ertugliflozin added to metformin:

• A1C: 0.7 percent (5 mg) and 0.9 percent (15 mg) (p<0.001 for both comparisons);

• FPG: 26.7 mg/dL (5 mg) and 38.3 mg/dL (15 mg) (p<0.001 for both comparisons);

• Body weight: 3.7 lbs (1.7 kg) (5 mg) and 3.5 lbs (1.6 kg) (15 mg) (p<0.001 for both comparisons);

• SBP: 3.7 mmHg (5 mg) (p=0.002) and 4.5 mmHg (15 mg) (p<0.001); and

• DBP: 1.8 mmHg (5 mg) (p=0.013) and 2.4 mmHg (15 mg) (p=0.001).

The incidence of adverse events was 42.5 percent, 50.2 percent and 45.0 percent in the ertugliflozin 5 mg and metformin, ertugliflozin 15 mg and metformin, and placebo and metformin groups, respectively.

A higher incidence of genital mycotic infections in females was observed in patients taking ertugliflozin 5 mg (5.5 percent) and 15 mg (6.3 percent) versus placebo (0.9 percent) (p=0.032 for 15 mg) and in males (3.1 percent (5 mg); 3.2 percent (15 mg); 0.0 percent (placebo)), added to metformin.

Ertugliflozin had no adverse impact on bone mineral density at week 26 (95 percent CI). Symptomatic urinary tract infections, hypoglycemia and hypovolemia adverse events were similar between treatment groups.

Results from VERTIS SITA: Initial Combination of Ertugliflozin and JANUVIA® (sitagliptin) (1197-P)

In this 26-week, randomized, double-blind investigational multicenter Phase 3 study of 291 patients with an A1C of 8.0 – 10.5 percent inadequately controlled with diet and exercise, patients were randomized to ertugliflozin 5 mg and sitagliptin 100 mg, ertugliflozin 15 mg and sitagliptin 100 mg or placebo.

The study met its primary endpoint of improved blood glucose control at 26 weeks with A1C reductions of 1.6 percent (ertugliflozin 5 mg and sitagliptin 100 mg), 1.7 percent (ertugliflozin 15 mg and sitagliptin 100 mg), compared with 0.4 percent in patients taking placebo (p<0.001 for both comparisons).

In addition, the study met a key secondary endpoint, with significantly more patients taking ertugliflozin 5 mg or 15 mg in combination with sitagliptin 100 mg achieving the A1C treatment goal of less than 7.0 percent (35.7 percent and 31.3 percent, respectively) compared with placebo (8.3 percent) (p<0.001, for both comparisons based on adjusted odds ratio comparisons).

The following statistically significant placebo-adjusted reductions were observed for the primary and additional key secondary endpoints:

• A1C: 1.2 percent (ertugliflozin 5 mg and sitagliptin 100 mg) and 1.2 percent (ertugliflozin 15 mg and sitagliptin 100 mg) (p<0.001 for both comparisons);

• FPG: 38.9 mg/dL for 5 mg ertugliflozin and 100 mg sitagliptin, 46.1 mg/dL for 15 mg ertugliflozin and 100 mg sitagliptin) (p<0.001 for both comparisons);

• 2-hour PMG: 62.4 mg/dL for ertugliflozin 5 mg and 100 mg sitagliptin and 69.6 mg/dL for ertugliflozin 15 mg and 100 mg sitagliptin (p<0.001 for both comparisons);

• Body weight: 4.4 lbs (2.0 kg) for ertugliflozin 5 mg and sitagliptin 100 mg and 4.6 lbs (2.1 kg) for ertugliflozin 15 mg and sitagliptin 100 mg (p<0.001 for both comparisons);

• SBP: 4.4 mmHg for ertugliflozin 5 mg and sitagliptin 100 mg (p=0.011) and 6.4 mmHg for ertugliflozin 15 mg and sitagliptin 100 mg (p<0.001).

Observed reductions in DBP were not significant (p>0.05). The incidence of adverse events was 44.9 percent, 44.8 percent and 42.3 percent in the ertugliflozin 5 mg and sitagliptin 100 mg, ertugliflozin 15 mg and sitagliptin 100 mg, and placebo groups, respectively.

A higher incidence of genital mycotic infections in males was observed in patients taking ertugliflozin 5 mg (5.3 percent) and 15 mg (1.9 percent) versus placebo (0.0 percent) and in females (4.9 percent (5 mg); 7.0 percent (15 mg); 5.0 percent (placebo)) (p≥0.05 for all comparisons). Incidence rates of urinary tract infections, symptomatic hypoglycemia and hypovolemia were low and not significantly different across groups.