Date: 2016-09-15
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the European Association for the Study of Diabetes Annual Meeting
Company: Merck&Co (USA - NJ) Pfizer (USA - NY)
Product: ertugliflozin
Action
mechanism: SGLT2 inhibitor.
Disease: type 2 diabetes
Therapeutic area: Metabolic diseases
Country:
Trial
details: VERTIS SITA2 is a part of the VERTIS clinical development program comprised of a total of nine Phase 3 trials in approximately 12,600 adults with type 2 diabetes. Results from the other six VERTIS trials will be submitted for publication and/or presentation at future scientific congresses.
Latest
news: * On September 15, 2016, Merck&Co, in partnership with Pfizer, announced that a Phase 3 study (VERTIS SITA2) of ertugliflozin, an investigational oral SGLT2 inhibitor for the treatment of patients with type 2 diabetes, met its primary endpoint. Both 5 mg and 15 mg daily doses of ertugliflozin showed significantly greater reductions in A1C* of 0.69 percent and 0.76 percent, respectively, compared with placebo (p<0.001, for both comparisons), when added to patients on a background of sitagliptin (100 mg/day) and stable metformin (?1500 mg/day). These study results were presented for the first time during an oral session today at the 52nd Annual Meeting of the European Association for the Study of Diabetes (EASD) in Munich, Germany. Merck&Co and Pfizer plan to submit New Drug Applications to the FDA for ertugliflozin and two fixed-dose combinations (ertugliflozin plus Januvia® (sitagliptin) and ertugliflozin plus metformin) by the end of 2016, with additional regulatory submissions outside of the U.S. to follow in 2017. In this double-blind, randomized, placebo-controlled study, 463 patients with type 2 diabetes and a baseline A1C of 7.0 – 10.5 percent were randomized to receive ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo in a 1:1:1 ratio. In addition to meeting the primary endpoint of reducing A1C at 26 weeks, ertugliflozin also met the following key secondary endpoints in the study: A greater proportion of patients taking ertugliflozin 5 mg and 15 mg achieved the A1C treatment goal of less than 7.0 percent (32.1 percent and 39.9 percent, respectively) compared with the placebo group (17.0 percent) (p<0.001, for both comparisons based on adjusted odds ratios); Overall adverse event (AE) rates were generally similar between ertugliflozin 5 mg (41.7 percent), ertugliflozin 15 mg (43.8 percent) and placebo (48.4 percent), with a similar rate of one or more serious AEs across all groups (4.5 percent for ertugliflozin 5 mg; 2.0 percent for ertugliflozin 15 mg; 3.3 percent for placebo). The rates of discontinuations due to AEs were low across all groups (3.2 percent for ertugliflozin 5 mg; 0.7 percent for ertugliflozin 15 mg; 0.7 percent for placebo). In the study, a higher incidence of genital mycotic infections was observed in patients taking ertugliflozin 5 mg and ertugliflozin 15 mg (males: 4.9 percent and 3.7 percent, respectively, vs. no events for placebo; females: 8.0 percent and 12.7 percent, respectively, vs. 1.9 percent for placebo). Urinary tract infection rates were low across the ertugliflozin 5 mg, ertugliflozin 15 mg and placebo groups (2.6 percent, 4.6 percent and 2.0 percent, respectively). Across groups, there were similar rates for symptomatic hypoglycemia (3.8 percent for ertugliflozin 5 mg; 0.7 percent for ertugliflozin 15 mg; 2.6 percent for placebo) and for hypovolemia adverse events (0.6 percent for ertugliflozin 5 mg; no events for ertugliflozin 15 mg; 0.7 percent for placebo). * On June 11, 2016, Merck&Co, in partnership with Pfizer announced that two Phase 3 studies (VERTIS Mono and VERTIS Factorial) of ertugliflozin met their primary endpoints. The study results showed statistically significant reductions in A1C (a measure of average blood glucose) for both ertugliflozin doses tested (5 mg and 15 mg daily). These results from the VERTIS clinical development program of ertugliflozin will be presented for the first time at the 76th Scientific Sessions of the American Diabetes Association, which are being held in New Orleans from June 10-14, 2016. A 26-week investigational study (VERTIS Mono), which evaluated ertugliflozin as monotherapy, met its primary endpoint, showing that patients randomized to ertugliflozin 5 mg and 15 mg had significantly greater A1C reductions of 0.99 percent and 1.16 percent, respectively, compared with placebo (p<0.001, for both comparisons). In addition, significantly more patients taking ertugliflozin 5 mg and 15 mg achieved the A1C treatment goal of less than 7.0 percent (28.2 percent and 35.8 percent, respectively) compared with placebo (13.1 percent) (p<0.001, for both comparisons), which was a secondary endpoint of the study. VERTIS Factorial, another 26-week investigational study, evaluated the co-administration of ertugliflozin and Merck’s DPP-4 inhibitor Januvia® (sitagliptin). This study also met its primary endpoint, with greater reductions in A1C observed in patients taking ertugliflozin in combination with sitagliptin compared to ertugliflozin or sitagliptin alone. An A1C reduction of 1.5 percent was observed in both combinations studied (ertugliflozin 5 mg or 15 mg with sitagliptin 100 mg), as compared with A1C reductions of 1.0 percent with ertugliflozin 5 mg alone, 1.1 percent with ertugliflozin 15 mg alone, and 1.1 percent with sitagliptin 100 mg alone (p<0.001 for both combinations vs. individual treatments). In addition, the co-administration of ertugliflozin and sitagliptin was significantly more effective than ertugliflozin or sitagliptin alone in achieving the A1C treatment goal of less than 7.0 percent, which was a secondary endpoint of the study. Specifically, 52.3 percent of patients taking ertugliflozin 5 mg in combination with sitagliptin 100 mg and 49.2 percent of patients taking ertugliflozin 15 mg in combination with sitagliptin 100 mg reached an A1C goal of less than 7.0 percent. In comparison, 26.4 percent achieved this A1C goal with ertugliflozin 5 mg, 31.9 percent with ertugliflozin 15 mg, and 32.8 percent with sitagliptin 100 mg (p<0.001 for both combinations vs. individual treatments in model-based tests). Results from VERTIS Mono: Ertugliflozin as a Monotherapy (130-LB): In this randomized, double-blind, placebo-controlled investigational study, 461 patients with type 2 diabetes and a baseline A1C of 7.0 – 10.5 percent, inclusive, who were inadequately controlled on diet and exercise alone and who had an eGFR (estimated glomerular filtration rate) of ?55 mL/min/1.73m2, were randomized to receive ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo in a 1:1:1 ratio. In addition to meeting the primary endpoint of improved blood glucose control at 26 weeks and the secondary endpoint of achieving an A1C treatment goal of less than 7.0 percent, the following observations were made on additional secondary endpoints: Placebo-adjusted mean significant reduction in body weight of 3.9 lbs (1.76 kg) (5 mg) and 4.8 lbs (2.16 kg) (15 mg) (p<0.001, for both comparisons); Results from VERTIS Factorial: Ertugliflozin When Combined with JANUVIA (Sitagliptin) (125-LB): In the randomized, double-blind investigational study, 1,233 patients with type 2 diabetes with a baseline A1C of 7.5 – 11.0 percent who were inadequately controlled on metformin alone (?1500 mg/day) and who had an eGFR (estimated glomerular filtration rate) of ?60 mL/min/1.73m2, were randomized to one of five treatment groups in a 1:1:1:1:1 ratio: co-administration of ertugliflozin 5 mg with sitagliptin 100 mg; co-administration of ertugliflozin 15 mg with sitagliptin 100 mg; ertugliflozin 5 mg; ertugliflozin 15 mg; or sitagliptin 100 mg. In addition to meeting the primary endpoint of improved blood glucose control at 26 weeks and the secondary endpoint of achieving an A1C treatment goal of less than 7.0 percent, the study also showed that the co-administration of ertugliflozin and sitagliptin was significantly more effective than ertugliflozin or sitagliptin alone in reducing FPG, and significantly more effective in reducing body weight and systolic blood pressure compared to sitagliptin alone, which were secondary endpoints. The following results on these secondary endpoints were observed: Patients taking ertugliflozin 5 mg and sitagliptin 100 mg experienced a reduction in FPG of 44.0 mg/dL (p?0.004 vs. ertugliflozin 5 mg and p<0.001 vs. sitagliptin); 48.7 mg/dL with ertugliflozin 15 mg and sitagliptin 100 mg (p<0.001 vs. each individual treatment); 35.7 mg/dL with ertugliflozin 5 mg; 36.9 mg/dL with ertugliflozin 15 mg; and 25.6 mg/dL with sitagliptin 100 mg. The incidence of genital mycotic infections was higher in patients receiving ertugliflozin compared to sitagliptin alone (females, 4.9-7.6 percent vs. 1.1 percent, and males, 2.4-4.7 percent vs. 0 percent).
Placebo-adjusted mean reduction in body weight of 4.4 lbs (2.0 kg) for the 5 mg dose and 3.7 lbs (1.7 kg) for the 15 mg dose (p<0.001, for both comparisons);
Placebo-adjusted mean reductions in fasting plasma glucose (FPG) of 25.1 mg/dl (1.4 mmol/L) for the 5 mg dose and 31.3 mg/dl (1.7 mmol/L) for the 15 mg dose (p<0.001, for both comparisons);
Placebo-adjusted mean reductions in systolic blood pressure of 2.9 mmHg (5 mg, p=0.019) and 3.9 mmHg (15 mg, p=0.002).
Placebo-adjusted mean significant reductions in fasting plasma glucose (FPG) of 34.50 mg/dL (5 mg) and 44.01 mg/dL (15 mg) (p<0.001, for both comparisons);
Placebo-adjusted mean significant reductions in postprandial glucose (PPG) of 69.03 md/dL (5 mg) and 67.33 mg/dL (15 mg) (p<0.001, for both comparisons); and
Numerically greater reductions in systolic blood pressure (3.31 mmHg (5 mg), 1.71 mmHg (15 mg)) and diastolic blood pressure (1.80 mmHg (5 mg), 0.37 mmHg (15 mg)), which did not reach statistical significance, for both comparisons.
Overall adverse event (AE) rates were similar between ertugliflozin 5 mg (52.6 percent), ertugliflozin 15 mg (55.9 percent) and placebo (52.3 percent), with a similar rate of one or more serious AEs across all groups (4.5 percent for ertugliflozin 5 mg; 1.3 percent for ertugliflozin 15 mg; 1.3 percent for placebo). The rates of discontinuations due to AEs were low across all groups (2.6 percent for ertugliflozin 5 mg; 2.0 percent for ertugliflozin 15 mg; 3.3 percent for placebo). A higher incidence of genital mycotic infections in females was observed in patients taking ertugliflozin 15 mg (22.6 percent) and ertugliflozin 5 mg (16.4 percent) compared with placebo (5.6 percent). There was no increase in the incidence of urinary tract infections with either dose of ertugliflozin relative to placebo.
The co-administration of ertugliflozin 5 mg and sitagliptin 100 mg resulted in a reduction in body weight of 5.5 lbs (2.5 kg); 6.4 lbs (2.9 kg) with ertugliflozin 15 mg and sitagliptin 100 mg; and 1.5 lbs (0.7 kg) with sitagliptin 100 mg (p<0.001 for both combinations vs. sitagliptin). Patients taking ertugliflozin alone, 5 or 15 mg, also experienced a reduction in body weight of 5.9 lbs (2.7 kg) and 8.1 lbs (3.7 kg), respectively.
Patients taking ertugliflozin 5 mg and sitagliptin 100 mg also experienced a reduction in systolic blood pressure of 3.4 mmHg (p=0.005 vs. sitagliptin); 3.7 mmHg with ertugliflozin 15 mg and sitagliptin 100 mg (p=0.002 vs. sitagliptin); and 0.7 mmHg with sitagliptin 100 mg. Patients taking ertugliflozin 5 or 15 mg alone also experienced a reduction in systolic blood pressure of 3.9 and 3.7 mmHg, respectively.
The incidence of AEs was similar across all therapeutic groups in the study (51.2 percent for ertugliflozin 5 mg; 43.1 percent for ertugliflozin 15 mg; 41.7 percent for sitagliptin 100 mg; 45.7 percent for ertugliflozin 5 mg plus sitagliptin 100 mg; 46.7 percent for ertugliflozin 15 mg plus sitagliptin 100 mg). The rates of serious AEs were similar across all groups (3.2 percent for ertugliflozin 5 mg; 1.2 percent for ertugliflozin 15 mg; 1.6 percent for sitagliptin 100 mg; 2.5 percent for ertugliflozin 5 mg plus sitagliptin 100 mg; 1.6 percent for ertugliflozin 15 mg plus sitagliptin 100 mg). The rates of discontinuations due to AEs were similar across the five treatment arms (2.4 percent for ertugliflozin 5 mg; 1.2 percent for ertugliflozin 15 mg; 0.4 percent for sitagliptin 100 mg; 1.2 percent for ertugliflozin 5 mg plus sitagliptin 100 mg; 2.9 percent for ertugliflozin 15 mg plus sitagliptin 100 mg).
