Merck and Pfizer Announce Investigational Ertugliflozin Met Primary Endpoint of A1C Reduction When Added to Sitagliptin and Metformin
OREANDA-NEWS. Merck (NYSE: MRK), known as MSD outside the United States and Canada, in partnership with Pfizer Inc. (NYSE: PFE) today 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 and Pfizer plan to submit New Drug Applications to the U.S. Food and Drug Administration 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.
“It is encouraging to see further data from the VERTIS clinical development program in support of combining ertugliflozin, an SGLT2 inhibitor, with the DPP-4 inhibitor sitagliptin, which was first approved 10 years ago,” said Peter Stein, M.D., vice president, late stage development, diabetes and endocrinology, Merck.
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);
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).
“We are pleased to share these new data on investigational ertugliflozin with the scientific community, following the first presentations of Phase 3 data for ertugliflozin at the American Diabetes Association’s 76th Scientific Sessions in June,” said James Rusnak, M.D., Ph.D., chief development officer, cardiovascular & metabolics, Pfizer. “Type 2 diabetes is a progressive disease and these study results help support the clinical profile of ertugliflozin as an add-on therapy for patients who may require multiple treatment combinations to help reach their blood sugar goals.”
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).
About the VERTIS Clinical Development Program for Ertugliflozin
In addition to the VERTIS MONO and VERTIS FACTORIAL studies, which were presented at the 76th Scientific Sessions of the American Diabetes Association, 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.
Important Information about JANUVIA® (sitagliptin) 25 mg, 50 mg and 100 mg tablets
JANUVIA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. JANUVIA has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk of developing pancreatitis while taking JANUVIA.
Selected Important Risk Information about JANUVIA®
JANUVIA is contraindicated in patients with a history of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema.
There have been postmarketing reports of acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, in patients taking JANUVIA. After initiating JANUVIA, observe patients carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue JANUVIA and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk of developing pancreatitis while taking JANUVIA.
Assessment of renal function is recommended prior to initiating JANUVIA and periodically thereafter. A dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with end-stage renal disease requiring hemodialysis or peritoneal dialysis. Caution should be used to ensure that the correct dose of JANUVIA is prescribed.
There have been postmarketing reports of worsening renal function, including acute renal failure, sometimes requiring dialysis. A subset of these reports involved patients with renal insufficiency, some of whom were prescribed inappropriate doses of sitagliptin.
When JANUVIA was used in combination with a sulfonylurea or insulin, medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo. Therefore, a lower dose of sulfonylurea or insulin may be required to reduce the risk of hypoglycemia.
The incidence (and rate) of hypoglycemia based on all reports of symptomatic hypoglycemia were: 12.2% (0.59 episodes/patient-year) for JANUVIA 100 mg in combination with glimepiride (with or without metformin), 1.8% (0.24 episodes/patient-year) for placebo in combination with glimepiride (with or without metformin), 15.5% (1.06 episodes/patient-year) for JANUVIA 100 mg in combination with insulin (with or without metformin), and 7.8% (0.51 episodes/patient-year) for placebo in combination with insulin (with or without metformin).
There have been postmarketing reports of serious hypersensitivity reactions in patients treated with JANUVIA, such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 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.
Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema with another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with JANUVIA®.
There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from 1 day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUVIA or with any other antidiabetic drug.
In clinical studies, the adverse reactions reported, regardless of investigator assessment of causality, in ?5% of patients treated with JANUVIA as monotherapy and in combination therapy and more commonly than in patients treated with placebo, were upper respiratory tract infection, nasopharyngitis, and headache.
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