Late Breaking Data Released at ADA

Late Breaking Data Released at ADA Showed that the Investigational Use of JANUVIA™ (sitagliptin) and Metformin as Initial Combination Therapy Provided Significant Glucose Lowering Efficacy over 54 Weeks in Patients with Type 2 Diabetes

Late breaking data presented at the American Diabetes Association (ADA) 67th Annual Scientific Sessions showed that, when used investigationally as initial therapy, JANUVIA™ (sitagliptin) in combination with metformin provided significant glycemic improvement and was generally well tolerated over 54 weeks in patients with type 2 diabetes. Additional new data from investigational studies presented also showed that JANUVIA significantly improved blood sugar control in patients with type 2 diabetes when added to a sulfonylurea, glimepiride (dual combination therapy), or when added to a sulfonylurea and metformin (triple combination therapy). Additional data were presented at the meeting regarding the efficacy and safety of JANUVIA.

JANUVIA is a selective, once-daily dipeptidyl peptidase-4 (DPP-4) inhibitor that enhances a natural body system, called the incretin system, which helps to regulate glucose by affecting the beta cells and alpha cells in the pancreas. JANUVIA is the first and only DPP-4 inhibitor to be approved and marketed in the United States for patients with type 2 diabetes. JANUVIA is indicated, as an adjunct to diet and exercise, to improve glycemic control in patients with type 2 diabetes mellitus. JANUVIA is also indicated to improve glycemic control, in combination with metformin or a thiazolidinedione (TZD), in patients with type 2 diabetes when the single agent alone plus diet and exercise do not provide adequate glycemic control. JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. There are no contraindications for JANUVIA.

Sitagliptin is also a component of JANUMET™ (sitagliptin/metformin HCl), the first and only tablet combining a DPP-4 inhibitor and metformin for the treatment of type 2 diabetes. JANUMET is indicated, as an adjunct to diet and exercise, to improve glycemic control in adult patients with type 2 diabetes who are not adequately controlled on metformin or sitagliptin alone or in patients already being treated with the combination of sitagliptin and metformin. Consistent with the labeling for metformin alone, JANUMET is contraindicated in patients with renal disease, renal dysfunction, or abnormal creatinine clearance; and acute or chronic metabolic acidosis, including diabetic ketoacidosis. JANUMET should not be used in patients with type 1 diabetes. Consistent with the labeling for metformin alone, the labeling for JANUMET contains a boxed warning for lactic acidosis, a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with JANUMET.

Initial combination therapy with JANUVIA and metformin significantly improved blood sugar control compared with metformin alone over one year (LB-04; Study #036)
This study demonstrated a mean A1C reduction from baseline of 1.8 percent in patients treated with JANUVIA 50 mg/metformin 1000 mg twice daily for up to 54 weeks (n=153). Additionally, mean A1C reductions from baseline were 1.4 percent in patients treated with JANUVIA 50 mg/metformin 500 mg twice daily (n=147), 1.3 percent in patients treated with metformin 1000 mg twice daily (n=134), 1.0 percent in patients treated with metformin 500 mg twice daily (n=117), and 0.8 percent in patients treated with JANUVIA 100 mg once daily (n=106).

After completing an initial 24-week placebo-controlled phase (n=1091) ("Phase A"), 762 patients with a mean baseline A1C of 8.7 percent continued in a 30-week, double-blind, active-controlled phase ("Phase B") on their previous active treatments: JANUVIA 50 mg/metformin 1000 mg twice daily (n=161); JANUVIA 50 mg/metformin 500 mg twice daily (n=160); metformin 1000 mg twice daily (n=153); metformin 500 mg twice daily (n=147); and JANUVIA 100 mg once-daily (n=141).

Two-thirds (67 percent) of patients continuing past 24 weeks in this study achieved the ADA target A1C goal of less than seven percent on JANUVIA 50 mg/metformin 1000 mg twice daily (n=153) compared to 44 percent on metformin 1000 mg twice daily alone (n=134). Further, 48 percent of patients treated with JANUVIA 50 mg/metformin 500 mg twice daily (n=147), 25 percent of patients treated with metformin 500 mg twice daily (n=117), and 23 percent of patients treated with JANUVIA 100 mg once daily (n=106) reached the ADA target A1C goal.

Duration of response was demonstrated by data showing that 85 percent of patients treated with JANUVIA 50 mg/metformin 1000 mg twice daily and 70 percent of patients treated with JANUVIA 100 mg once daily who achieved the target A1C goal of less than seven percent at Week 24 had a Week 54 A1C value of less than seven percent (n=96 and 33, respectively). In addition, 80 percent of patients treated with JANUVIA 50 mg/metformin 500 mg twice daily (n=65), 79 percent of patients treated with metformin 1000 mg twice daily (n=63), and 59 percent of patients treated with metformin 500 mg twice daily (n=34) who reached a goal A1C of less than seven percent at Week 24 had a Week 54 A1C value of less than seven percent.

Over the 54 week study, five out of 182 patients (three percent) treated with JANUVIA 50 mg/metformin 1000 mg twice daily and two out of 182 patients (one percent) treated with metformin 1000 mg twice daily had at least one episode of hypoglycemia. Incidences of gastrointestinal adverse experiences were similar to those observed with metformin alone (26 percent vs. 31 percent with metformin 1000 mg twice daily).

"Initial therapy with one agent is often unsuccessful at getting patients to blood sugar goals. Many patients may require initial combination therapy, and this study provides important and useful information about the use of sitagliptin and metformin, in addition to diet and exercise, in order to achieve and maintain blood sugar control," said John Amatruda, M.D., vice president, clinical research, Merck & Co., Inc. "This study examines the clinical effect of initial combination therapy with JANUVIA and metformin, the two drugs comprising JANUMET, over one year."

An important predictive factor of the magnitude of A1C reduction in response to anti-hyperglycemic therapy is a patient's starting level of A1C. In a subgroup analysis of patients grouped by severity of starting baseline A1C, treatment with JANUVIA 50 mg/metformin 1000 mg twice daily demonstrated increasing mean A1C reductions from baseline the higher the baseline A1C. A mean reduction of 3.1 percent was seen in patients with baseline A1C of 10 percent or more (n=17), while reductions of 2.2 percent, 1.7 percent, and 1.0 percent were seen with baseline A1C values of nine to 10 percent, eight to nine percent, and less than eight percent, respectively.

Investigational study showed JANUVIA significantly improved blood sugar control when added to sulfonylurea or to sulfonylurea and metformin vs. sulfonylurea or sulfonylurea and metformin alone (Poster #535-P; Study #035)
In this study, which was designed to examine the efficacy and safety of JANUVIA in patients with type 2 diabetes whose blood glucose levels were inadequately controlled (A1C levels of 7.5 percent to 10.5 percent) on a sulfonylurea (glimepiride) alone or on a sulfonylurea (glimepiride) plus metformin, JANUVIA demonstrated a significant mean difference from placebo in A1C of 0.9 percent in patients on glimepiride and metformin and 0.6 percent in patients on glimepiride alone (p<0.001 for both comparisons to the addition of placebo).

After a titration/stabilization period on glimepiride (at least 4 mg/day) with or without metformin (at least 1500 mg/day) and a 2-week placebo run-in, 441 patients with a mean baseline A1C of 8.3 percent were randomized to the addition of JANUVIA 100 mg once-daily or placebo for 24 weeks. Of these patients, 212 were on glimepiride alone (106 each on JANUVIA or placebo), and 229 on glimepiride and metformin (116 on JANUVIA, 113 on placebo). The primary endpoint was A1C change from baseline for the entire cohort.

The addition of JANUVIA to a sulfonylurea with or without metformin was generally well-tolerated in this study. A higher incidence of overall adverse experiences (60 vs. 47 percent) and drug-related adverse experiences (15 vs. 7 percent) were reported with JANUVIA compared to placebo in patients treated with glimepiride with or without metformin. These higher rates were partly related to a higher incidence of hypoglycemia with JANUVIA compared to placebo (12 vs. 2 percent, respectively). The higher rate of hypoglycemia has commonly been seen when antihyperglycemic agents are used in combination with sulfonylurea agents. After 24 weeks, body weight was increased more with JANUVIA than with placebo (mean change from baseline of +0.8 vs. -0.4 kg, respectively; p<0.001).

"These new potential uses of sitagliptin as add-on to sulfonylurea, as add-on to sulfonylurea plus metformin, and as initial therapy in combination with metformin, if approved by the FDA, would provide physicians with additional treatment options for patients with type 2 diabetes," said Mark Kipnes, M.D., associate medical director, Diabetes and Glandular Research Associates, and clinical professor of Medicine, University of Texas Health Science Center at San Antonio.

As Merck announced in February, these data have been submitted to the U.S. Food and Drug Administration (FDA) in support of proposed new indications for the use of JANUVIA. One sNDA is filed in support of a proposed new indication for the use of JANUVIA, as an adjunct to diet and exercise, in combination with metformin as initial therapy to improve glycemic control. The other sNDA is filed in support of two proposed new indications for use of JANUVIA, as an adjunct to diet and exercise, as add-on therapy to a sulfonylurea when the single agent alone does not provide adequate glycemic control and as add-on therapy to the combination of a sulfonylurea plus metformin when dual therapy does not provide adequate glycemic control. The FDA is reviewing the sNDA for these indications and Merck expects FDA action by mid-October.

A pooled analysis of 5,141 patients showed overall incidence of adverse experiences, incidence of serious adverse experiences, and incidence of discontinuations due to adverse experiences were similar in the JANUVIA and non-exposed groups for up to two years (Poster #534-P)
The safety and tolerability of JANUVIA was assessed by pooling data from nine completed Phase IIB and III studies, including the studies discussed above, ranging from 24 to 104 weeks in duration, and including 5,141 patients treated with either JANUVIA 100 mg daily (n=2,786) or other treatments (placebo or an active comparator) (n=2,355). The studies assessed JANUVIA as monotherapy, initial combination therapy with metformin, or add-on to another oral agent (metformin, pioglitazone, sulfonylurea, or sulfonylurea and metformin).

JANUVIA 100 mg daily was generally well-tolerated as monotherapy, as initial combination therapy, or as add-on therapy. For adverse experiences (either clinical or laboratory), the overall incidence of adverse experiences, the incidence of serious adverse experiences, and the incidence of discontinuations due to adverse experiences were similar in the JANUVIA treated patients and in patients who received other therapies (patients on placebo or active comparator). Drug-related adverse experiences were higher in the non-exposed group due to hypoglycemia reported in sulfonylurea-treated patients (since studies in which a sulfonylurea agent was a treatment in patients not receiving JANUVIA were included in this pooled analysis).

Specific clinical adverse experiences, expressed as a rate of ≥1 event per 100 patient-years of exposure, in the JANUVIA population included nasopharyngitis [12 vs. 9], hypoglycemia [9 vs. 58], increased blood glucose [5 vs. 9], osteoarthritis [2 vs. 1], contact dermatitis [1 vs. <1], tremor [1 vs. <1], nasal congestion [1 vs. <1], and reduced blood glucose [1 vs. 3] for JANUVIA and non-exposed patients, respectively.

Dosing of JANUVIA
The recommended dose of JANUVIA is 100 mg once daily, with or without food, for all approved indications. No dosage adjustment is needed for patients with mild to moderate hepatic insufficiency or in patients with mild renal insufficiency (CrCl ≥50 mL/min). To achieve plasma concentrations of JANUVIA similar to those in patients with normal renal function, lower dosages are recommended in patients with moderate and severe renal insufficiency as well as in end-stage renal disease (ESRD) patients requiring hemodialysis. For patients with moderate renal insufficiency (CrCl ≥30 to <50 mL/min), the dose of JANUVIA is 50 mg once daily. For those with severe renal insufficiency (CrCl <30 mL/min) or with ESRD requiring dialysis, the dose of JANUVIA is 25 mg once daily. Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter.

Dosing of JANUMET
JANUMET should be given twice daily with meals, with gradual dose escalation as needed to reduce the gastrointestinal (GI) side effects due to metformin. In this formulation, the dose of sitagliptin remains constant (100 mg daily) and is combined with the two most widely prescribed doses of metformin (1000 mg daily or 2000 mg daily). The recommended starting dose of JANUMET for patients not on prior metformin therapy and for those not adequately controlled on sitagliptin is 50 mg sitagliptin and 500 mg metformin twice-daily with meals. For patients already receiving metformin therapy, the starting dose should be based on the patient's current metformin regimen. The total daily dose should not exceed 100 mg sitagliptin and 2000 mg metformin.

Metformin and sitagliptin are known to be substantially excreted by the kidney. The risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive JANUMET. In the elderly, JANUMET should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging can be associated with reduced renal function. Any dose adjustment should be based on a careful assessment of renal function. Before initiation of therapy with JANUMET and at least annually thereafter, renal function should be assessed and verified as normal.

Selected cautionary information for JANUVIA
Because JANUVIA is renally eliminated, and to achieve plasma concentrations of JANUVIA similar to those in patients with normal renal function, a dosage adjustment is recommended in patients with moderate renal insufficiency and in patients with severe renal insufficiency or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis. Safety and effectiveness of JANUVIA in pediatric patients have not been established. There are no adequate and well-controlled studies in pregnant women. JANUVIA should be used during pregnancy only if clearly needed. Caution should be exercised when JANUVIA is administered to a nursing woman. In clinical trials, JANUVIA demonstrated an overall incidence of side effects comparable to placebo. The most common side effects reported with JANUVIA (≥5 percent and higher than placebo) were stuffy or runny nose and sore throat, upper respiratory infection, and headache.

Selected cautionary information for JANUMET
JANUMET should be avoided in patients with evidence of hepatic disease. Before initiation of therapy with JANUMET and at least annually thereafter, renal function should be assessed and verified as normal. Patients should be warned against excessive alcohol intake while receiving JANUMET. Patients may require discontinuation of JANUMET and temporary use of insulin during periods of stress and decreased intake of fluids and food such as may occur with fever, trauma, infection or surgery. Patients previously controlled on JANUMET who develop laboratory abnormalities or clinical illness should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). When lactic acidosis occurs, it is fatal in approximately 50 percent of cases.

Expanding clinical development program for sitagliptin family
Merck's clinical development program for sitagliptin is robust and continues to expand with 47 studies completed or under way, and nine more studies set to begin this year. There have been more than 7,600 patients in the Company's clinical studies with about 4,700 of these patients, being treated with sitagliptin. Additionally, about 1,900 patients have been treated with sitagliptin for more than a year.

About Merck
Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com