PRESS RELEASE: Merck's Januvia Wins New Uses but Risks Outlined

Merck's Januvia Wins New Uses but Risks Outlined

WHITEHOUSE STATION, N.J. -- Merck & Co., Inc. today announced that the U.S. Food and Drug Administration (FDA) has approved expanded labeling for JANUVIA(TM) (sitagliptin), the only DPP-4 inhibitor available in the United States for the treatment of type 2 diabetes. JANUVIA is indicated, as an adjunct to diet and exercise, to improve glycemic control in adult patients with type 2 diabetes. JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. JANUVIA has not been studied in combination with insulin. The new regimens with JANUVIA described in the updated labeling include, as an adjunct to diet and exercise, initial therapy in combination with metformin; add-on therapy to a sulfonylurea (glimepiride) when the single agent alone does not provide adequate glycemic control; and, add-on therapy to the combination of a sulfonylurea (glimepiride) and metformin when dual therapy does not provide adequate glycemic control.

New data contained in three studies support the efficacy and safety of JANUVIA. Initial therapy with the combination of JANUVIA and metformin provided substantial A1C reductions. JANUVIA demonstrated similar efficacy to a sulfonylurea (glipizide) in patients inadequately controlled on metformin. JANUVIA also provided significant placebo-adjusted A1C reductions in patients being treated with a sulfonylurea (glimepiride), with or without metformin.

The expanded labeling for JANUVIA was also updated, within Warnings and Precautions, to include post-marketing reports of hypersensitivity reactions in patients treated with JANUVIA. These reactions include anaphylaxis, angioedema and exfoliative skin conditions including Stevens-Johnson syndrome. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The expanded labeling also includes a contraindication for patients with history of a serious hypersensitivity reaction to sitagliptin, including anaphylaxis and angioedema.

Since its initial approval in October 2006, over two million prescriptions have been written for JANUVIA. In controlled clinical studies as both monotherapy and combination therapy with metformin or pioglitazone, the overall incidence of adverse reactions, hypoglycemia, and discontinuation of therapy due to clinical adverse reactions with JANUVIA were similar to placebo. In these clinical studies, the most common adverse reactions reported with JANUVIA (greater than or equal to 5 percent and higher than placebo) were stuffy or runny nose and sore throat, upper respiratory infection and headache. In clinical trials in combination with a sulfonylurea (glimepiride), with or without metformin, JANUVIA demonstrated an overall incidence of adverse reactions higher than that seen with placebo, in part related to a higher incidence of hypoglycemia.

Initial therapy with the combination of JANUVIA and metformin provides significantly greater A1C reductions with a similar GI tolerability profile compared to metformin alone

JANUVIA as initial therapy in combination with metformin is supported by a randomized, double-blind, placebo-controlled factorial study in 1,091 patients with type 2 diabetes who experienced inadequate glycemic control with diet and exercise alone. In this study, the mean reduction of A1C relative to placebo at 24 weeks was 2.1 percent with initial therapy combining JANUVIA 100 mg daily and metformin 2000 mg daily(1) (n=178) from a mean baseline A1C of 8.8 percent (p less than 0.001). The mean placebo-adjusted A1C reductions in the other arms of the study were 1.6 percent with JANUVIA 100 mg daily and metformin 1000 mg daily(2) (n=183); 1.3 percent with metformin 2000 mg daily(3) (n=177); 1.0 percent with metformin 1000 mg(4) daily (n=178); and 0.8 percent with JANUVIA (n=175), (pless than 0.001 for all treatment groups versus placebo).

At 24 weeks, 66 percent of patients treated with the initial combination of JANUVIA 100 mg daily and metformin 2000 mg daily achieved the American Diabetes Association's (ADA) goal A1C level of less than 7 percent vs. 38 percent of patients treated with metformin 2000 mg daily alone. In the other arms of the study, 43 percent of patients treated with JANUVIA 100 mg daily and metformin 1000 mg daily, 23 percent of patients treated with metformin 1000 mg daily, and 20 percent of patients treated with JANUVIA achieved the ADA goal A1C level of less than 7 percent. This study also included an open label cohort of an additional 117 patients with severely elevated baseline A1C (mean: 11.2 percent). These patients experienced a significant mean A1C reduction from baseline of 2.9 percent at 24 weeks with initial therapy combining JANUVIA 100 mg daily and metformin 2000 mg daily.

This study also compared the efficacy of JANUVIA to two common doses of metformin in a subset of patients not on any anti-hyperglycemic agent at study entry. In this patient population, patients treated with JANUVIA experienced a mean A1C reduction from baseline of 1.1 percent compared to 1.1 percent in patients treated with metformin 1000 mg daily and 1.2 percent in patients treated with metformin 2000 mg daily.

"The substantial A1C reductions that are seen when JANUVIA is used in combination with metformin as first-line therapy in patients with type 2 diabetes are meaningful to me as a clinician. The data show that this approach helped many patients achieve their A1C goal and the rate of gastrointestinal side effects was similar to that seen with metformin alone," said Barry J. Goldstein, M.D., Ph.D., professor of medicine, Biochemistry and Molecular Pharmacology; director, Division of Endocrinology, Diabetes and Metabolic Diseases, Jefferson Medical College, Philadelphia, PA.

Initial combination therapy or maintenance of combination therapy may not be appropriate for all patients. These management options are left to the discretion of the physician.

In the factorial study, initial therapy with JANUVIA and metformin was not associated with an increased risk of gastrointestinal adverse reactions beyond those commonly seen with metformin alone. In a pooled analysis of four other placebo-controlled clinical studies with JANUVIA, not including initial therapy with JANUVIA and metformin, the incidence of selected gastrointestinal adverse reactions in patients treated with JANUVIA was abdominal pain (2.3 percent JANUVIA; 2.1 percent placebo); nausea (1.4 percent JANUVIA; 0.6 percent placebo); and diarrhea (3.0 percent JANUVIA; 2.3 percent placebo).

The incidence of hypoglycemia was similar across treatment groups (0.6 percent in patients on placebo, 0.6 percent in patients given JANUVIA alone, 0.8 percent in patients given metformin alone, and 1.6 percent in patients given JANUVIA in combination with metformin). The most common adverse reactions reported with JANUVIA and metformin as initial therapy (greater than or equal to 5 percent) compared to metformin alone were upper respiratory infection (6.2 percent vs. 5.2 percent) and headache (5.9 percent vs. 3.8 percent).

JANUVIA demonstrated similar efficacy compared to a sulfonylurea (glipizide) with significantly less hypoglycemia, and patients treated with JANUVIA experienced mean weight loss from baseline of 1.5 kg

The efficacy of JANUVIA was also evaluated in a 52-week, double-blind, glipizide-controlled noninferiority trial predominantly in patients with mildly to moderately elevated A1C levels (mean baseline A1C 7.5 percent). Patients were treated with either JANUVIA 100 mg daily or glipizide up to 20 mg daily (mean daily dose 10 mg daily). This study showed that JANUVIA achieved the pre-specified bounds for noninferiority vs. a sulfonylurea (glipizide). After one year, the mean A1C reduction from baseline was 0.5 percent for JANUVIA and 0.6 percent for glipizide in the intent-to-treat patient population(5) and 0.7 percent for JANUVIA and 0.7 percent for glipizide in the per protocol analysis(6), confirming the similar efficacy of JANUVIA compared to glipizide.

Patients treated with JANUVIA experienced significant weight loss (mean -1.5 kg) from baseline at 52 weeks, while patients treated with glipizide experienced significant weight gain (mean +1.1 kg) from baseline at 52 weeks. Additionally, patients treated with JANUVIA experienced a lower incidence of hypoglycemia than patients treated with glipizide (4.9 percent vs. 32.0 percent, respectively, p less than 0.001). The noninferiority of JANUVIA to glipizide may be limited to patients with A1C levels comparable to those included in this study (over 70 percent of patients had a baseline A1C less than 8 percent and over 90 percent had a baseline A1C less than 9 percent).

JANUVIA provides significant additional A1C reductions, even in patients on triple therapy

The new regimens for adding JANUVIA to a sulfonylurea (glimepiride) with or without metformin are supported by a 24-week, randomized, double-blind, placebo-controlled study examining the efficacy and safety of JANUVIA in 441 patients with type 2 diabetes and inadequate glycemic control (A1C 7.5 percent to 10.5 percent) on a sulfonylurea (glimepiride) and metformin or on a sulfonylurea (glimepiride) alone. In this study, JANUVIA demonstrated a significant mean difference from placebo in A1C of -0.9 percent when added to patients on glimepiride and metformin and -0.6 percent when added to patients on glimepiride alone (p less than 0.001 for both comparisons versus placebo).

In this study, the overall incidence of clinical adverse reactions with JANUVIA was higher than that seen with placebo, in part related to a higher incidence of hypoglycemia with JANUVIA compared to placebo (12.2 percent vs. 1.8 percent, respectively). The higher rate of hypoglycemia is commonly seen when antihyperglycemic agents are used in combination with sulfonylurea agents. After 24 weeks, patients treated with JANUVIA had a mean increase in body weight of 1.1 kg versus placebo (+0.8 kg vs. -0.4 kg).

As is typical with other anti-hyperglycemic agents used in combination with a sulfonylurea, when JANUVIA is used in combination with a sulfonylurea, a class of medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo. Therefore, a lower dose of sulfonylurea may be required to reduce the risk of hypoglycemia.

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 greater than or equal to 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 greater than or equal to 30 to less than 50 mL/min), the dose of JANUVIA is 50 mg once daily. For those with severe renal insufficiency (CrCl less than 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.

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 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. It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when JANUVIA is administered to a nursing woman. There have been post-marketing reports of hypersensitivity reactions in patients treated with JANUVIA. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Onset of these reactions occurred within the first three months after initiation of treatment with JANUVIA, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue JANUVIA, assess for other potential causes for the event and institute alternative treatment for diabetes.

Expanding clinical development program for sitagliptin family

Merck's clinical development program for sitagliptin is robust and continues to expand with 49 studies completed or underway. Five additional studies are set to begin this year. It is estimated that there have been more than 9,400 patients in the Company's clinical studies, with about 6,000 of these patients being treated with sitagliptin. Additionally, about 2,300 patients have been treated with sitagliptin for more than a year and, of these, approximately 400 patients have been treated for at least two years.

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 [1].

Merck forward-looking statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2006, and in its periodic reports on Form 10-Q and Form 8-K, which the Company incorporates by reference.