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- Positive opinion 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 a conclusive signal of efficacy in the prevention of the primary endpoint.

- If approved by the European Commission, canagliflozin will be the first therapy approved in nearly 20 years, since the approval of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), to slow the progression of diabetic kidney disease (DKD) in UK patients with type 2 diabetes mellitus (T2DM), including those with moderate and severe renal impairment.^[1]

- There are an estimated 4.2 million people in the UK living with T2DM, approximately 40% of whom will go on to develop kidney disease.^[2],[3]

- As commercial partner to the Marketing Authorization Holder Janssen Pharmaceutica NV, Napp Pharmaceuticals Limited has exclusive distribution rights for canagliflozin in the United Kingdom.

CAMBRIDGE, England, May 29, 2020 /PRNewswire/ -- As the exclusive UK distributor of Invokana^® (canagliflozin), Napp Pharmaceuticals Limited today announced that the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion to extend the indication of canagliflozin to include important renal outcome data from the landmark Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial.^[4]

If approved by the European Commission, canagliflozin would be the only SGLT2i approved to treat diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM) patients with an urinary albumin/creatinine ratio >300mg/g and estimated glomerular filtration rate [eGFR] down to 30ml/min/1.73m². This update will allow continued use until renal replacement therapy, recognising the cardiovascular and renal benefits of canagliflozin in T2DM even at an eGFR level <30ml/min/1.73m².^[5]

"The CHMP positive opinion is exciting news and highlights how diabetic kidney disease has become an integral part of type 2 diabetes management," said Dr Ogün Sazova, Napp Medical Director. "The opinion to extend the label to include patients who are likely to need renal replacement therapy means that Invokana will be available to slow the progression of diabetic kidney disease in this additional population of people with type 2 diabetes."

The CREDENCE trial is the first dedicated and published renal outcomes study in patients with DKD and T2DM. The study enrolled 4401 subjects with an eGFR of 30 to <90ml/min/1.73m² and albuminuria (urinary albumin: creatinine ratio >300 to 5000 mg/g). All patients were treated on a background of standard of care for DKD, including angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). 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]: 0.59 to 0.82; p<0.00001).^[5]

Rates of adverse events and serious adverse events were similar overall in the canagliflozin group and the placebo group. There were no observed differences in the incidence of lower limb amputations (12.3 vs 11.2 events per 1000 patient years; HR: 1.11; 95% CI: 0.79 to 1.56) or adjudicated bone fractures (11.8 vs 12.1 events per 1000 patient years; HR: 0.98; 95% CI: 0.70 to 1.37). The study was stopped early in July 2018, owing to positive efficacy findings.^[5] 

In the UK, canagliflozin is currently indicated for the treatment of adults with insufficiently controlled T2D and an eGFR of ?60 mL/min/1.73 m², 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.^[6] 

About the CREDENCE clinical trial

The CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) study was the first dedicated and fully recruited renal outcome 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, including 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.^[5]

About Invokana^®

Canagliflozin is a member of a class of drugs known as SGLT2 inhibitors, which acts independently of insulin. The kidneys act to filter the blood by removing and selectively reabsorbing chemicals, including glucose and sodium. An important transport carrier in the kidneys for the reabsorption of sodium and glucose is called SGLT2. Canagliflozin selectively inhibits SGLT2.^[7] 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. The effect of increased sodium uptake in this part of 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 can lead to nephron dysfunction.^[8]

Canagliflozin was first approved by European Union in 2013. It is currently licensed 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. The initiation dose is 100mg once daily in adults with an eGFR of ?60 mL/min/1.73 m² and can be increased to 300mg once daily if tighter glycaemic control is needed. Canagliflozin should not be initiated if eGFR is <60 mL/min/1.73m². In patients tolerating canagliflozin whose eGFR falls persistently below 60 mL/min/1.73m² the dose should be adjusted to or maintained at 100mg once daily. Canagliflozin should be stopped if eGFR falls persistently below 45 mL/min/1.73m². Approval was based on a comprehensive global Phase III clinical trial programme.^[6]

About type 2 diabetes

T2DM is a metabolic defect resulting in high levels of sugar (glucose) in the blood.^[9] T2DM 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. It is caused by a combination of sedentary lifestyle, unhealthy diet and/or genetic factors. A number of factors can increase the risk of developing T2DM, including obesity.^[9],[10] 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).^[10] 

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).^[10],[11]

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.

UK/INV-20078  |  May 2020

 References

[1] George Institute: CREDENCE results presentation Available at: https://view.publitas.com/george-institute/credence-trial-results-and-slides/page/1. Last accessed: April 2020.

[2] Diabetes UK. Facts and figures. Available at: https://www.diabetes.org.uk/resources-s3/2019-02/1362B_Facts%20and%20stats%20Update%20Jan%202019_LOW%20RES_EXTERNAL.pdf. Last accessed: April 2020.

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

[4] European Medicines Agency. Summary of CHMP Opinion recommendation for Invokana (canagliflozin) issued on 28^th May 2020. Available at https://www.ema.europa.eu/en/medicines/human/summaries-opinion/invokana Last accessed: May 2020.

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

[6] EMC. SmPC. Invokana 100 mg and 300 mg film-coated tablets. Available at: https://www.medicines.org.uk/emc/product/8855#INDICATIONS.  Last accessed: April 2020.

[7] 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: April 2020.

[8] 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

[9] Diabetes UK. Type 2 Diabetes. Available at: http://www.diabetes.co.uk/type2-diabetes.html. Last accessed: April 2020.

[10] Diabetes UK. Diabetes and obesity. Available at: https://www.diabetes.co.uk/diabetes-and-obesity.html. Last accessed: April 2020.

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

For more information please contact or visit:

Napp www.napp.co.uk

Hugh Adams
Email: hugh.adams@napp.co.uk
Tel: +44 (0)7855 106263

Roland Barter
Clark Health Communications
Email: roland@clarkhealthcomms.com 
Phone: +44 (0)7540 183755

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