First Results from Phase 3 CANVAS Trial Show Canagliflozin as Add-on Therapy to Insulin Lowered Blood Sugar Levels in Patients with Type 2 Diabetes at an Elevated Risk for Cardiovascular Disease

BERLIN, Oct. 2, 2012 /PRNewswire/ -- Janssen Research & Development, LLC (Janssen) today announced that use of the investigational medicine canagliflozin substantially lowered blood glucose levels when used as add-on therapy in patients on insulin therapy for type 2 diabetes and who are considered to be at greater risk for cardiovascular disease. These results were presented at the 48th European Association for the Study of Diabetes (EASD) Annual Meeting.

CANVAS (CANagliflozin cardioVascular Assessment Study), also known as DIA3008, is a prospective, double blind, placebo-controlled trial designed to evaluate the efficacy, tolerability and cardiovascular safety of canagliflozin in 4,330 adult patients with type 2 diabetes considered at elevated risk for cardiovascular disease. Cardiovascular disease is the leading cause of death in people with type 2 diabetes, and accounts for over 50% of type 2 diabetes fatalities.[1]

The data presented were from an 18-week sub-study of 1,718 patients enrolled in CANVAS who were receiving insulin for an average of 7.1 years. Patients in this sub-study who were randomized to treatment with daily canagliflozin 100 mg or 300 mg, in addition to their usual insulin regimen, had statistically greater A1C reductions at 18 weeks relative to placebo (percent change from baseline, -0.65 and -0.73%, respectively, p<0.001). The overall incidence of treatment-emergent adverse events (AEs) was generally similar across all treatment arms.

"Adults with type 2 diabetes are two to four times more likely to have heart disease or stroke compared to those who don't have diabetes," said David R. Matthews, FRCP, Professor of Diabetes, Oxford Centre for Diabetes, Endocrinology & Metabolism and co-lead investigator of the CANVAS (DIA3008) trial. "Effective management of type 2 diabetes in patients with elevated cardiovascular risk and other comorbidities can be challenging because these patients are often more susceptible to complications of the side effects of antihyperglycemic therapy. The results from this sub-study suggest that canagliflozin could provide an important new treatment option for higher-risk adult patients with type 2 diabetes."

In secondary efficacy endpoint measures in the CANVAS study, both the canagliflozin 100 mg and 300 mg dose groups provided reductions in body weight relative to placebo (body weight percent change, -1.9 and -2.4%, respectively, p<0.001). Reductions in fasting plasma glucose were consistent with the primary endpoint for canagliflozin 100 mg and 300 mg relative to placebo (-1.25 and -1.61 mmol/L, respectively, p<0.001). The study also met secondary end points including the following (for canagliflozin relative to placebo): reductions in systolic blood pressure with canagliflozin 100 mg and 300 mg (-2.6 and -4.4 mmHg, respectively, p<0.001); reductions in diastolic blood pressure with canagliflozin 100 mg and 300 mg (-1.0 and -1.8 mmHg, respectively); high-density lipoprotein cholesterol (HDL-C) increased with both 100 mg and 300 mg doses of canagliflozin relative to placebo, [percent change, 0.8% (0.02 mmol/L), p=0.46, and 4.7% (0.05 mmol/L), p<0.001, respectively] though the change was not statistically significant for the 100 mg dose; low-density lipoprotein cholesterol (LDL-C) rose with canagliflozin 100 mg and 300 mg [6.3% (0.03 mmol/L) and 6.6% (0.11 mmol/L), respectively); non statistically significant changes in triglycerides with canagliflozin 100 mg and 300 mg [0.2% (0.01 mmol/L), p=0.95, and -2.0% (-0.04 mmol/L), p=0.44, respectively]; and increases in total cholesterol levels with canagliflozin 100 mg and 300 mg [1.0% (0.05 mmol/L) and 3.3% (0.14 mmol/L), respectively]. These efficacy parameters are all important consideration in the disease management of patients with type 2 diabetes.

The incidence of AEs leading to discontinuation was greater with canagliflozin 300 mg (5.3%) compared to canagliflozin 100 mg or placebo (1.9% for both). Most AEs were assessed by the investigator as mild to moderate in intensity and the overall incidence of AEs was balanced across treatment arms. Adverse events of genital mycotic infections in men and women, increased urination (pollakiuria), and hypotension were more common with canagliflozin 100 mg and 300 mg compared to placebo in men and women; these specific adverse events were generally mild or moderate in intensity and infrequently led to discontinuation. A slightly higher incidence of urinary tract infections was seen with canagliflozin 300 mg than 100 mg or placebo. The incidence of hypoglycemia was higher with canagliflozin 100 mg and 300 mg than placebo (49 and 48% vs. 37%, respectively). These data were included in the New Drug Application (NDA) Janssen submitted to the U.S. Food and Drug Administration and the Marketing Authorization Application (MAA) to the European Medicines Agency seeking approval for the use of canagliflozin for the treatment of type 2 diabetes announced on May 31, 2012 and June 26, 2012, respectively.

In a second Phase 3 study also presented at EASD, canagliflozin significantly reduced A1C levels compared to placebo, when added to ongoing antihyperglycemic therapy in older patients with type 2 diabetes not having adequate glycemic control.

In this 26-week randomized, double-blind, placebo-controlled study known as DIA3010, 714 patients with a mean age of 63.6 years were given once-daily doses of canagliflozin (100 mg or 300 mg), or placebo. Patients treated with canagliflozin 100 mg and 300 mg doses had substantial and sustained decreases in A1C levels, and a significantly greater reduction relative to placebo after 26 weeks (-0.57 and -0.70%, respectively, p<0.001). The overall incidence of treatment-emergent AEs was similar with both canagliflozin 100 mg and 300 mg doses and placebo (71.8 and 78.0% vs. 73.4%, respectively).

"Assessing the tolerability and efficacy of new antihyperglycemic agents in patients with other comorbidities, such as cardiovascular disease, and in older patients is important because they are more vulnerable populations with a great need for effective and generally well-tolerated options. These data suggest canagliflozin may have utility in a wide range of patients with type 2 diabetes, including as add-on therapy in these more vulnerable patient populations," said Kirk Ways, M.D., Ph.D., Vice President and Compound Development Team Leader for canagliflozin at Janssen. "The breadth of the Phase 3 development program also reinforces our commitment to develop new therapeutic options for unmet patient needs in the treatment of type 2 diabetes."

In secondary efficacy endpoint measures from DIA3010, patients treated with canagliflozin 100 mg and 300 mg also had greater weight loss compared to placebo (-2.3 and -3.0%, respectively, p<0.001); reductions in fasting plasma glucose, relative to placebo, were consistent with the primary A1C endpoint (-1.4 and -1.5 mmol/L, respectively, p<0.001); systolic blood pressure was reduced with canagliflozin 100 mg and 300 mg compared to placebo (-4.6 and -7.9 mmHg, respectively, p<0.001). Canagliflozin 100 mg and 300 mg raised HDL-C relative to placebo [5.3% (0.06 mmol/L) and 4.7% (0.05 mmol/L), respectively, p<0.001)], and LDL-C [7.5% (0.13 mmol/L) and 7.8% (0.18 mmol/L), respectively]; reductions in diastolic blood pressure with canagliflozin 100 mg and 300 mg (-1.6 and -3.2 mmHg, respectively); decreased triglycerides with canagliflozin 100 mg (-4.8%) and increased triglyceride levels in patients receiving canagliflozin 300 mg (0.7%).

There were low rates of serious AEs (4.1 and 3.4% for canagliflozin 100 mg and 300 mg vs. 5.1% for placebo) and AE-related discontinuations (2.1 and 7.2% for canagliflozin 100 mg and 300 mg vs. 4.2% for placebo) across groups. Adverse events related to genital mycotic infections in men and women, osmotic diuresis-related events such as increased urination, and urinary tract infections were more frequent in patients treated with canagliflozin than placebo. These specific adverse events were generally mild or moderate in intensity and infrequently led to discontinuation. Overall, 74.1% of patients were on a background antihyperglycemic therapy that can lead to hypoglycemia (e.g. insulin and non–glucose-dependent insulin secretagogues); in those patients, hypoglycemia rates were somewhat higher with canagliflozin 100 mg and 300 mg than placebo (43.1 and 47.4% vs. 37.7%, respectively). In patients not on such agents the incidence of hypoglycemia episodes was low, with slightly higher rates observed for canagliflozin 100 mg and 300 mg compared to placebo (6.7 and 4.8%,vs. 3.2%, respectively); one patient in the canagliflozin 100 mg group experienced a severe hypoglycemia episode (1.7%).

These results are included in the following abstracts at EASD 2012:

• Efficacy and safety of canagliflozin, an inhibitor of sodium glucose co-transporter 2 (SGLT2), added-on to insulin therapy +/- oral agents in type 2 diabetes (Abstract 764)
• Efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor (SGLT2), in older subjects with type 2 diabetes mellitus (Abstract 765)

About Canagliflozin
Canagliflozin is an investigational sodium glucose co-transporter 2 (SGLT2) inhibitor for the treatment of patients with type 2 diabetes. The kidneys of people with type 2 diabetes reabsorb greater amounts of glucose back into the body compared to non-diabetic people, which may contribute to elevated glucose levels. Canagliflozin blocks the reabsorption of glucose by the kidney, increasing glucose excretion and lowering blood glucose levels.

The global Phase 3 canagliflozin clinical program, which enrolled 10,285 patients in nine studies, is the largest late-stage development program for an investigational pharmacologic product for the treatment of type 2 diabetes submitted to health authorities to date. The program evaluated the safety and efficacy of canagliflozin across the spectrum of type 2 diabetes management, from adult patients treated only with diet and exercise to those requiring insulin injections to maintain glycemic control, and in three large studies in special populations: older patients with type 2 diabetes, patients with type 2 diabetes who have had moderate renal impairment, and patients with type 2 diabetes who had or were at high risk for developing cardiovascular disease.

Janssen and its affiliates have rights to canagliflozin through a license agreement with Mitsubishi Tanabe Pharma Corporation. Janssen Pharmaceuticals, Inc. and its affiliates have marketing rights in North America, South America, Europe, Middle East, Africa, Australia, New Zealand and parts of Asia.

About Janssen
At Janssen, we are dedicated to addressing and solving some of the most important unmet medical needs of our time in oncology, immunology, neuroscience, infectious diseases and vaccines, and cardiovascular and metabolic diseases. Driven by our commitment to patients, we develop innovative products, services and healthcare solutions to help people throughout the world. Janssen Research & Development, LLC and Janssen Pharmaceuticals, Inc. are part of the Janssen Pharmaceutical Companies of Johnson & Johnson. Please visit http://www.janssenrnd.com for more information.

(This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen Research & Development, LLC and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to, general industry conditions and competition; economic factors, such as interest rate and currency exchange rate fluctuations; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approvals; challenges to patents; changes in behavior and spending patterns or financial distress of purchasers of healthcare products and services; changes to governmental laws and regulations and domestic and foreign health care reforms; trends toward health care cost containment; and increased scrutiny of the healthcare industry by government agencies. A further list and description of these risks, uncertainties and other factors can be found in Exhibit 99 of Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended January 1, 2012. Copies of this Form 10-K, as well as subsequent filings, are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. Neither Janssen Research & Development, LLC nor Johnson & Johnson undertake to update any forward-looking statements as a result of new information or future events or developments.

[1] Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H. Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes. Diabetologia 2001;44 Suppl 2:S14-S21.

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SOURCE Janssen Research & Development, LLC

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