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Napp Pharmaceuticals Announces European Commission Approval of Invokana® (canagliflozin) Label Update to Reflect Improved Renal Outcomes in Patients With Diabetic Kidney Disease and Type 2 Diabetes

July 2, 2020 Off By BusinessWire

The European Commission (EC) approval is based on the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) Phase III renal outcomes trial, which was stopped early based on the achievement of a pre-specified efficacy criterion.
Canagliflozin is the first therapy approved in nearly 20 years to slow the progression of diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM), including patients with moderate and severe renal impairment.¹
There are an estimated 4.2 million people in the UK living with T2DM,² approximately 40% of whom will go on to develop kidney disease.³
Diabetes is estimated to cost the NHS £14 billion per year,⁴ and over 80% of those costs are the result of managing complications of the disease, such as DKD.⁵

CAMBRIDGE, England–(BUSINESS WIRE)–Napp Pharmaceuticals Limited today announced that the European Commission (EC) has approved the extension of the indication of Invokana^® (canagliflozin) to include important renal outcome data from the landmark Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, which was the first dedicated renal outcomes trial in patients with diabetic kidney disease (DKD) and Type 2 diabetes mellitus (T2DM).⁶ Canagliflozin is now the only sodium-glucose co-transporter 2 inhibitor (SGLT2i) approved with an extended indication to treat DKD in T2DM patients.⁶

For the first time in Europe, T2DM patients with an estimated glomerular filtration rate (eGFR) of ≥45 to <60 mL/min/1.73m² can now be initiated on SGLT2i treatment with Invokana^® 100 mg.⁷ In addition, T2DM patients with albuminuria (urinary albumin: creatinine ratio >30 mg/mmol (>300mg/g)) and an eGFR ≥30 mL/min/1.73m² can now be initiated on Invokana^® 100 mg and also maintained on treatment until dialysis or renal transplantation.⁷

Professor Vlado Perkovic, Study Author and Professorial Fellow at the George Institute, Australia, Dean of Medicine at UNSW Sydney commented: “Canagliflozin is the first medical breakthrough in nearly 20 years proven to slow the progression of chronic kidney disease in patients with diabetes at high risk of developing kidney failure. These impressive results from the CREDENCE study have significant clinical implications for preventing kidney failure and have now been incorporated in major kidney, diabetes and cardiovascular guidelines globally. They provide an opportunity to significantly improve the health of millions of people living with chronic kidney disease and type 2 diabetes. (Read more…) With the new approval by The European Commission, these benefits can be realised by people across Europe.”

People with diabetes are five times more likely to need dialysis or a kidney transplant than those without.² In the UK, diabetes is the leading cause of kidney failure,⁸ affecting 10,350 people with diabetes.² Therefore, slowing the rate of progression of DKD is critical to the successful management of T2DM and its known co-morbidities.

“Today’s label change for canagliflozin marks a significant milestone for T2DM patients with DKD, as there have been no new treatment advances to slow the progression of kidney disease in nearly 20 years,” said Dr Ogün Sazova, Napp Medical Director. “Napp is delighted that the decision means that steps can be put in place to slow kidney disease progression, leading to marked improvements in outcomes for the 40% of T2DM patients who go on to develop kidney disease.”

The CREDENCE trial is the first dedicated renal outcomes study in patients with DKD and T2DM. The study enrolled 4,401 subjects with an eGFR of 30 to <90mL/min/1.73m² and albuminuria (urinary albumin: creatinine ratio >300 to 5000 mg/g).¹ Importantly, all patients were treated on a background of standard of care for DKD, in the form of a maximum tolerated dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB).¹ The results showed that canagliflozin demonstrated a 30% reduction, compared to placebo, in the risk of the primary composite endpoint, comprising end-stage renal disease (ESRD), doubling of serum creatinine and renal or cardiovascular (CV) death, with event rates of 43.2 vs 61.2 per 1000 patient years, respectively (Hazard Ratio [HR]: 0.70; 95% Confidence Interval [CI]: 0.57–0.84; p<0.0001).⁷

Rates of adverse events and serious adverse events were similar overall in the canagliflozin group and the placebo group.¹ There were no statistical differences in the incidence of lower limb amputations (HR: 1.11; 95% CI, 0.79–1.56; ARR: 1 more event per 1,000 patient-years) or adjudicated bone fractures (HR: 0.98; 95% CI, 0.70–1.37; ARR: 0).¹ There was a small but increased risk of diabetic ketoacidosis observed in the canagliflozin group (HR: 10.80; 95% CI: 1.39–83.65; ARR: 2.0 more events per 1,000 patient-years), compared with the placebo group. The study was stopped early in July 2018, owing to positive efficacy findings.¹

Canagliflozin has been approved in the UK since November 2013.⁷ The recommended starting dose for T2DM is 100 mg once-daily.⁷ In patients tolerating this dose and with an eGFR ≥60 mL/ min/1.73m² needing tighter glycaemic control, the dose can be increased to 300 mg once daily.⁷ In patients tolerating canagliflozin whose eGFR falls persistently below 60 mL/min/1.73m², the dose of canagliflozin should be adjusted to, or maintained at, 100 mg once daily.⁷ Canagliflozin should be discontinued when eGFR is persistently below 45 mL/min/1.73m².⁷ For the treatment of DKD as an add-on to standard of care (e.g. ACE-inhibitors or ARBs), a dose of 100 mg canagliflozin once daily should be used.⁷ In patients with severely increased albuminuria (urinary albumin: creatinine ratio >30 mg/mmol (>300mg/g)) canagliflozin can be initiated if eGFR ≥30 mL/min/1.73 m² and used until renal replacement therapy or transplantation.⁷ As commercial partner to the Marketing Authorization Holder Janssen Pharmaceutica NV, Napp Pharmaceuticals Limited has exclusive distribution rights for canagliflozin in the United Kingdom.

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About the CREDENCE clinical trial¹

The CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) study was the first dedicated and fully recruited renal outcomes trial evaluating renal and cardiovascular outcomes in people with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) with a sodium glucose co-transporter 2 (SGLT2) inhibitor. It was a phase III randomised, double-blind, event-driven, placebo-controlled, parallel-group, two-arm multicentre study of the effects of canagliflozin on renal and cardiovascular outcomes in subjects with T2DM and CKD. In particular, it compared the efficacy and safety of canagliflozin versus placebo in preventing clinically important kidney and cardiovascular outcomes in patients with T2DM and CKD when used in addition to standard of care, in the form of a maximum tolerated daily dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). The study was stopped early in July 2018 owing to positive efficacy findings.

About Invokana^®

Canagliflozin is a member of a class of drugs known as SGLT2 inhibitors, which act independently of insulin.⁹ The kidneys act to filter the blood by removing and selectively reabsorbing chemicals, including glucose and sodium.⁹ An important transport carrier in the kidneys for the reabsorption of sodium and glucose is called SGLT2. Canagliflozin selectively inhibits SGLT2.⁹ The inhibition of SGLT2 promotes the loss of glucose via the urine, lowering glucose levels in adults with T2DM, and also increases sodium uptake in a region of the nephron called the macula densa.¹⁰ The effect of increased sodium uptake in this part of the nephron is the constriction of the afferent arteriole supplying blood to the nephron. This lowers the blood pressure to the nephron, thereby reducing damage to the fine arterioles in the glomerulus, which could otherwise lead to nephron dysfunction.¹⁰

Canagliflozin was approved in the European Union by the European Commission in November 2013.⁷ It is indicated for the treatment of adults with insufficiently controlled T2DM as an adjunct to diet and exercise, as monotherapy when metformin is considered inappropriate due to intolerance or contraindications and in addition to other medicinal products for the treatment of diabetes.⁷

The recommended initiation dose of canagliflozin is 100 mg once daily in adults with an eGFR of ≥ 60 mL/min/1.73m² and can be increased to 300 mg once daily if tighter glycaemic control is needed.⁷ For treatment of DKD as add on to standard of care in patients with an eGFR of 45 to <60 mL/min/1.73m² the initiation dose is 100mg once daily.⁷ If further glycaemic control is needed the addition of other anti-hyperglycaemic agents should be considered.⁷ In patients with an eGFR of 30 to <45 mL/min/1.73m² with severe albuminuria (urinary albumin: creatinine ratio ˃30 mg/mmol (>300mg/g)), the initiation dose is 100 mg once daily.⁷ Canagliflozin should not be initiated if eGFR is below 30 mL/min/1.73m², but for patients already taking canagliflozin it can be continued at 100 mg until dialysis or renal transplantation is required.⁷

About Type 2 diabetes

Type 2 diabetes mellitus is a metabolic defect resulting in high levels of sugar (glucose) in the blood.¹¹ It is one of the most common long-term health conditions in the UK and typically occurs in older and overweight patients, though it is now being seen in ever-younger patients.¹¹ It is caused by a combination of sedentary lifestyle, unhealthy diet and/or genetic factors.¹¹ A number of factors can increase the risk of developing T2DM, including obesity.¹² Obesity, specifically excess abdominal fat, can make the body less sensitive to insulin, causing a resistance by disrupting the function of insulin responsive cells and therefore the cells’ ability to respond to insulin, leading to higher blood sugar levels (hyperglycaemia).¹²

If not well controlled, T2DM can lead to long-term complications such as; heart disease, stroke, kidney damage (nephropathy), eye disease (retinopathy) and peripheral nerve damage (neuropathy).^12,13

About Napp Pharmaceuticals Ltd

Napp Pharmaceuticals Limited is a UK pharmaceutical company established in the 1920’s and based in the heart of the Cambridge science community. Focused principally in the areas of diabetes, respiratory, cancer, arthritis and gastroenterology, we have worked side-by-side with the NHS since its inception. As the UK healthcare environment has evolved, so has Napp, ensuring we have the right expertise to mirror what the NHS needs from us, understanding NHS priorities and what influences and drives decision-making.

We are part of a worldwide network of independent companies, which gives us the flexibility to make locally driven decisions quickly. We have developed our working practices to ensure we can be agile, and act fast and efficiently, in order to help our partners deliver sustainable healthcare solutions that ultimately improve patient outcomes. We aim to bring value-added medicines to the NHS by building effective partnerships. This is innate in the way we work because we are a partnership-based organisation, placing it at the heart of everything we do and every relationship, from our wholesale distributors to NHS decision-makers.

We are extremely proud of our heritage in partnership working, which is centred around building and developing mutually beneficial, enduring partnerships that are open and based on respect – this is how we have built our reputation as a partner of choice.

References

¹ Perkovic, V. et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019; 380:2295–2306.

² Diabetes UK. Us, Diabetes and lots of Facts and Stats. Available at: https://www.diabetes.org.uk/resources-s3/2019-02/1362B_Facts%20and%20stats%20Update%20Jan%202019_LOW%20RES_EXTERNAL.pdf. Last accessed: July 2020.

³ Diabetes UK. Diabetic Nephropathy – Kidney Disease. Available at: https://www.diabetes.co.uk/diabetes-complications/kidney-disease.html. Last accessed: June 2020.

⁴ Diabetes.co.uk. Cost of Diabetes. Available at: https://www.diabetes.co.uk/cost-of-diabetes.html. Last accessed: July 2020.

⁵ Diabetes UK. Cost of Diabetes Report. Available at: https://www.diabetes.org.uk/resources-s3/2017-11/diabetes%20uk%20cost%20of%20diabetes%20report.pdf. Last accessed: July 2020.

⁶ The European Commission. Union Register of medicinal products for human use. Product Information. Available at: https://ec.europa.eu/health/documents/community-register/html/h884.htm. Last accessed: July 2020.

⁷ EMC. SmPC. Invokana 100 mg and 300 mg film-coated tablets. Available at: https://www.medicines.org.uk/emc/product/8855/smpc. Last accessed July 2020.

⁸ Kidney Research UK. Diabetes. Available at: https://kidneyresearchuk.org/conditions-symptoms/diabetes/. Last accessed: July 2020.

⁹ European Medicines Agency. EPAR Summary for the Public: Invokana canagliflozin. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/002649/WC500156455.pdf. Last Accessed: July 2020.

¹⁰ Vallon, V., Thomson, S.C. The tubular hypothesis of nephron filtration and diabetic kidney disease. Nat Rev Nephrol. 2020; 16:317–336. https://doi.org/10.1038/s41581-020-0256-y.

¹¹ Diabetes.co.uk. Type 2 Diabetes. Available at: http://www.diabetes.co.uk/type2-diabetes.html. Last accessed: July 2020.

¹² Diabetes.co.uk. Diabetes and obesity. Available at: https://www.diabetes.co.uk/diabetes-and-obesity.html. Last accessed: July 2020.

¹³ Update to International Diabetes Federation, 2016. Complications of Diabetes. Available at: https://www.idf.org/aboutdiabetes/what-is-diabetes/complications.html. Last accessed: July 2020.