INVOKANA® (canagliflozin) Significantly Reduces the Combined Risk of Cardiovascular Death, Myocardial Infarction, and Stroke in the CANVAS Programme

Janssen-Cilag International NV today announced results from the CANVAS Programme which showed INVOKANA ^® (canagliflozin) when added to standard of care significantly reduced the combined risk of cardiovascular (CV) death, nonfatal myocardial infarction (MI), and nonfatal stroke by 14%, versus placebo in patients with type 2 diabetes mellitus (T2DM) at risk for or with a history of CV disease. The results also showed canagliflozin treatment was associated with a reduced risk of hospitalisation for heart failure and demonstrated potential renal protective effects. These data from the integrated analysis of the CANVAS and CANVAS-R trials were published in the New England Journal of Medicine, and presented in a special symposium at the American Diabetes Association 77^th Scientific Sessions on Monday, June 12^th, in San Diego, CA.

Canagliflozin was studied in one of the largest completed CV outcomes programme of any sodium glucose cotransporter-2 (SGLT2) inhibitor. The CANVAS Programme is the first to assess the long-term efficacy and safety of canagliflozin in more than 10,000 patients with T2DM, who had either a prior history of CV disease, or at least two CV risk factors.

The International Diabetes Federation estimates that, in 2015, over 59 million people were living with diabetes in Europe.¹ If left uncontrolled, T2DM can lead to serious long-term microvascular and macrovascular complications.

Canagliflozin achieved a 14% reduction in the risk of the composite primary endpoint of CV death, nonfatal MI, or nonfatal stroke (Hazard Ratio - HR: 0.86; 95% Confidence Interval - CI: 0.75 to 0.97), and demonstrated an improved cardiovascular safety profile compared to placebo (p<0.0001 for non-inferiority) and superiority compared to placebo (p=0.0158). Each component evenly contributed to this risk reduction, including nonfatal MI by 15% (HR: 0.85; 95% CI: 0.69 to 1.05), CV death by 13% (HR: 0.87; 95% CI: 0.72 to 1.06), and nonfatal stroke by 10% (HR: 0.90; 95% CI: 0.71 to 1.15). These outcomes were broadly consistent across various patient subgroups, and across the individual components of the primary endpoint.²

Additional analysis further revealed canagliflozin lowered the risk of hospitalization for heart failure by 33% (HR: 0.67; 95% CI: 0.52 to 0.87) and provided sustained positive effects on glycemic and blood pressure control, as well as weight reduction, demonstrating wide-ranging durability.²

In addition, canagliflozin showed potential renal protective effects, delaying progression of albuminuria and reducing the risk of clinically important renal composite outcomes (such as 40% reduction of estimated glomerular filtration rate (eGFR), renal death, or renal replacement therapy) by 40% (HR: 0.60; 95% CI: 0.47 to 0.77). The ongoing, fully enrolled CREDENCE study, the first dedicated SGLT2 inhibitor renal outcome trial in patients with T2DM and kidney disease, is further evaluating the effects of canagliflozin on renal and CV outcomes.

“Patients with diabetes are two to four times more likely to suffer from associated comorbidities such as heart failure and kidney disease, and the CANVAS results demonstrate the potential of canagliflozin in reducing the risk for such conditions in high-risk type 2 diabetes patients,” said David Matthews, CANVAS Steering Committee co-chair, and Professor of Diabetic Medicine and Honorary Consultant Physician, University of Oxford. “These data are promising as they suggest canagliflozin may offer potential benefits for patients with type 2 diabetes, who are also facing complications from, or are at risk for, hospitalization for heart failure or kidney disease.”

Overall adverse events seen in the CANVAS Programme were consistent with previous findings. An increased risk of amputation with canagliflozin was seen in both the completed CANVAS study and in the CANVAS-R study. This is consistent with the observation made by the study’s Independent Data Monitoring Committee (IDMC) in 2016, and the data shared with Health Authorities and Health Care Professionals. There was an increased risk of amputation (6.3 vs. 3.4/1000 patient-years) corresponding to a hazard ratio (HR) of 1.97. The highest absolute risk of amputation occurred in patients with a prior history of amputation or peripheral vascular disease, but the relative risk for amputation with canagliflozin was comparable across these subgroups. A warning of the potential increased risk of toe amputation is being included in the prescribing information for SGLT2 inhibitors in the European Union and the risk has been included in the canagliflozin EU Summary of Product Characteristics (SmPC).

Separately, while an increased risk of adjudicated low trauma fracture was identified in the CANVAS study, no increase was observed in the CANVAS-R study. A full assessment is ongoing to provide a complete safety review of the CANVAS and CANVAS-R results.

“The results of the CANVAS Programme are extremely exciting for us at Janssen and the wider diabetes community,” said Jose Antonio Buron Vidal, Vice-President Medical Affairs, Janssen Europe, Middle-East and Africa. “Janssen has an ongoing commitment to address unmet needs in the treatment of type 2 diabetes and the positive and broad benefit-risk profile demonstrated here with canagliflozin reinforces our commitment to exploring the potential of canagliflozin in additional patient populations.”

-ENDS-

NOTES TO EDITORS

About Type 2 Diabetes

Type 2 diabetes is a chronic condition that affects the body’s ability to metabolise sugar, or glucose, and is characterised by the inability of pancreatic beta cell function to keep up with the body’s demand for insulin.

The International Diabetes Federation estimates that, in 2015, 415 million people globally were living with diabetes (type 1 and 2), and this diabetes population is expected to grow to over 642 million by 2040.³ In 2015, it was estimated that over 59 million people were living with diabetes in Europe.¹ The World Health Organisation (WHO) estimates that 90% of the diabetes population have type 2 diabetes.⁴

If left uncontrolled, type 2 diabetes can lead to serious long-term microvascular and macrovascular complications. Improved glycemic control has been demonstrated to reduce the onset and progression of these complications.

About the CANVAS Programme

The CANVAS Programme is composed of two, nearly-identical large outcomes studies CANVAS (CANagliflozin CardioVascular Assessment Study, (NCT01032629)) and CANVAS-R (Study of the Effects of Canagliflozin on Renal Endpoints in Adult Subjects with T2DM, (NCT01989754)).

The CANVAS Programme is one of the largest completed CV outcomes programmes of any SGLT2 inhibitor to date, with a total of 10,142 patients – 4,330 patients in CANVAS and 5,812 patients in CANVAS-R. In the randomised, placebo-controlled Phase 3/4 studies, the vast majority of patients were obese, with a history of hypertension, and 66% of patients had a history of CV disease (14% had a history of heart failure) and 34% of patients had at least two CV risk factors. The study assessed the safety of canagliflozin relative to placebo in patients receiving specific commonly-used diabetes agents. The primary endpoint was defined as major adverse CV events (MACE), composed of nonfatal MI, nonfatal stroke, and CV death, and the secondary endpoint was defined as progression of albuminuria, beta-cell function, estimated glomerular filtration rate (eGFR) changes and Urine Albumin-to-Creatinine Ratio (UACR).

In the CANVAS study, subjects were randomly assigned in a 1:1:1 ratio to placebo, canagliflozin 100mg and canagliflozin 300mg. The mean and median exposure to investigational product was approximately 4.3 and 5.8 years, respectively. The mean and median follow-up time was 5.7 and 6.1 years, respectively.

In the CANVAS-R study, which involved similar population as the CANVAS study (in adults with type 2 diabetes who had inadequate glycemic control and who had or were considered to be at high risk for cardiovascular disease), subjects were randomly assigned in a 1:1 ratio to placebo or canagliflozin 100mg (with an investigator option to up-titrate to 300mg if the subject required additional glycemic control, provided the 100mg dosage was well tolerated). The mean and median exposure to investigational product was approximately 1.8 and 1.9 years, respectively. The mean and median follow-up time was 2.1 years.

These CANVAS and CANVAS-R studies were designed to be highly similar in patient population, procedures and assessments, evaluating the effects of canagliflozin on CV events in a similar study population. This approach is demonstrated in three published studies: “Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)—A randomized placebo-controlled trial,” published online by American Heart Journal; “Rationale, design and baseline characteristics of the CANagliflozin cardioVascular Assessment Study–Renal (CANVAS-R): A randomized, placebo-controlled trial," published online by Diabetes, Obesity and Metabolism ; and “Optimizing the analysis strategy for the CANVAS Programme – a pre-specified plan for the integrated analyses of the CANVAS and CANVAS-R trials,” published online by Diabetes, Obesity and Metabolism.

About canagliflozin

In 2013, INVOKANA^® (canagliflozin) was approved in the European Union for the treatment of adults with type 2 diabetes mellitus (T2DM), to improve glycaemic control either as a monotherapy or add-on therapy. The European approval of canagliflozin was based on a comprehensive global Phase 3 clinical trial Programme, which enrolled 10,285 patients in nine studies^{.5,6,7,8,9,10,11,12,13,14}

INVOKANA^® (canagliflozin) is a prescription medicine used along with diet and exercise to lower blood sugar in adults with type 2 diabetes. INVOKANA^® is not for people with type 1 diabetes or with diabetic ketoacidosis (increased ketones indicated in blood or urine). It is not known if INVOKANA^® is safe and effective in children under 18 years of age. Canagliflozin does not have an indication for CV risk reduction.

Janssen Pharmaceuticals, Inc. 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 Africa, parts of Asia, Australia, Europe, the Middle East, New Zealand, North America and South America.

INVOKANA^® is approved as a single agent in Aruba, Australia, Brazil, Canada, Chile, Colombia, Costa Rica, Curacao, Dominican Republic, El Salvador, the European Union (28 countries), Guatemala, Hong Kong, Iceland, India, Israel, Jamaica, Kazakhstan, Kuwait, Lebanon, Liechtenstein, Mexico, New Zealand, Nicaragua, Norway, Panama, Paraguay, Peru, Philippines, Qatar, Russia, Serbia, Singapore, South Korea, Switzerland, Thailand, United Arab Emirates and the United States.

IMPORTANT SAFETY INFORMATION

The most common side effects of INVOKANA^® include: hypoglycemia in combination with insulin or a sulphonylurea; vaginal yeast infections and yeast infections of the penis; and changes in urination, including need to urinate more often, in larger amounts, or at night.

Other side effects include: Dehydration (which may cause dizziness, faintness, lightheadedness or weakness on standing (orthostatic hypotension)); Diabetic Ketoacidosis; Urinary Tract Infections; and Changes in Kidney function.

A warning of the potential increased risk of toe amputation is being included in the prescribing information for SGLT2 inhibitors in the European Union and the risk has been included in the canagliflozin EU Summary of Product Characteristics (SmPC).

About the Janssen Pharmaceutical Companies

At the Janssen Pharmaceutical Companies of Johnson & Johnson, we are working to create a world without disease. Transforming lives by finding new and better ways to prevent, intercept, treat and cure disease inspires us. We bring together the best minds and pursue the most promising science. We are Janssen. We collaborate with the world for the health of everyone in it. Learn more at www.janssen.com /emea. Follow us on www.twitter.com/JanssenEMEA for our latest news.

Cautions Concerning Forward-Looking Statements

This press release contains “forward-looking statements” as defined in the Private Securities Litigation Reform Act of 1995 regarding product development. 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 known or unknown risks or uncertainties materialise, actual results could vary materially from the expectations and projections of Janssen-Cilag International NV and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; product efficacy or safety concerns resulting in product recalls or regulatory action; changes in behaviour and spending patterns or financial distress of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended January 1, 2017, including in the sections captioned “Cautionary Note Regarding Forward-Looking Statements,” and “Item 1A. Risk Factors,” and the company's subsequent filings with the Securities and Exchange Commission. Copies of these filings are available online at www.sec.gov , www.jnj.com or on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies and Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.

References:

¹ IDF Diabetes Atlas, 7th edn. Brussels, Belgium: International Diabetes Federation, 2015. Available at: http://www.diabetesatlas.org/ Last accessed June 2017.

² Neal B et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes, 2017; The New England Journal of Medicine

³ International Diabetes Federation. About Diabetes. Available at: https://www.idf.org/about-diabetes/what-is-diabetes.html Last accessed June 2017.

⁴ Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus. Geneva, World Health Organization, 1999 (WHO/NCD/NCS/99.2)

⁵ INVOKANA SmPC. Available at: http://ec.europa.eu/health/documents/community-register/2017/20170428137649/anx_137649_en.pdf Last accessed June 2017.

⁶ Lavalle-González FJ et al. Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial. Diabetologia. 2013;56(12):2582-92

⁷ Schernthaner G et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial. Diabetes Care. 2013; 36(9):2508-15

⁸ Cefalu WT et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet. 2013; 382(9896):941-50.

⁹ Bode B et al. Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: a randomized trial. Hosp Pract. 2013;41(2):72-84.

¹⁰ Yale JF et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab. 2013;15(5):463-73.

¹¹ Neal B, Perkovic V, et al. (2013). Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)—A randomized placeboc ontrolled trial. American Heart Journal; 166(2): 217-223

¹² Stenlof et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013;15(4):372-82.

¹³ Wilding JP et al. Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial. Int J Clin Pract. 2013;67(12):1267-82

¹⁴ Forst T et al. Efficacy and Safety of Canagliflozin in subjects with Type 2 Diabetes on Metformin and Pioglitazone. Poster presented at the 4th World Congress on Controversies to Consensus in Diabetes, Obesity and Hypertension (CODHy), 2012;Nov.8-11; Barcelona, Spain, (P64).

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