Forxiga (Dapagliflozin) Receives CHMP Positive Opinion for Chronic Kidney Disease Treatment in the EU – First SGLT2 Inhibitor Approved Regardless of Diabetes Status

Kidney (Image source: thehealthsite.com)

June 29, 2021 / Bioon -- AstraZeneca recently announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion recommending approval of the SGLT2 inhibitor Forxiga (Chinese trade name: Andatang, generic name: dapagliflozin) for the treatment of adult patients with chronic kidney disease (CKD), with or without type 2 diabetes (T2D). The CHMP's opinion will now be submitted to the European Commission (EC) for review, which is expected to make a final decision within the next two months. If approved, Forxiga has the potential to transform the treatment paradigm for millions of CKD patients across the European Union.

In late April this year, Forxiga (U.S. brand name: Farxiga) received U.S. FDA approval for the treatment of adult patients with chronic kidney disease (CKD) at risk of disease progression, to reduce the risk of sustained decline in estimated glomerular filtration rate (eGFR), end-stage kidney disease (ESKD), cardiovascular (CV) death, and hospitalization for heart failure (hHF). This indication covers patients with or without type 2 diabetes (T2D). Notably,Farxiga is the first SGLT2 inhibitor approved for the treatment of patients with CKD (with or without T2D). This approval marks the most significant advancement in the treatment of CKD in over 20 years.

Forxiga is also indicated for: (1) as an adjunct to diet and exercise to improve glycemic control in adult patients with T2D; (2) in adult patients with heart failure with reduced ejection fraction (HFrEF) (with or without T2D) to reduce the risk of cardiovascular death and hospitalization for heart failure.In China, these two indications were approved in March 2017 and February 2021, respectively.

CKD is a serious progressive disease characterized by declining kidney function, which is often associated with an increased risk of heart disease or stroke, or the need for dialysis or kidney transplantation. CKD affects approximately 47 million people in the European Union and nearly 840 million people worldwide. However, the diagnosis rate of CKD remains low, with up to 90% of patients unaware that they have the disease. It is projected that by 2040, CKD will become the fifth leading cause of death globally.

CHMP's positive opinion, based on the results of the pivotal Phase 3 DAPA-CKD trial. Data showed that, when added to standard of care therapy (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers),Compared with placebo, treatment with Forxiga demonstrated an unprecedented reduction in the risk of the composite endpoint of worsening renal function, end-stage kidney disease (ESKD), cardiovascular death, or renal death. Compared with placebo, Forxiga also significantly reduced the risk of death from any cause.In this trial, the safety and tolerability of Forxiga were consistent with the known safety profile of the drug.

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D at AstraZeneca, said: “The unprecedented results from the DAPA-CKD Phase 3 trial demonstrate that Forxiga can significantly slow the decline of kidney function in patients with CKD and reduce the risk of death. This positive CHMP opinion highlights the potential of Forxiga to transform the future of CKD care, bringing us one step closer to providing a much-needed new treatment option to millions of patients across the European Union.”

DAPA-CKD Clinical Data Results (Image sourced from publication PMID: 32970396, click image to enlarge)

DAPA-CKD was an international, multicenter, randomized, double-blind trial designed to evaluate the effect of Forxiga 10 mg versus placebo, in addition to standard of care, on renal outcomes and cardiovascular mortality in patients with chronic kidney disease (CKD), with or without type 2 diabetes. The study was conducted across 21 countries and enrolled 4,245 patients with stage 2–4 CKD and increased urinary protein excretion, with or without type 2 diabetes. Patients were randomized to receive once-daily Forxiga or placebo, alongside standard of care. The primary composite endpoint was the risk of worsening renal function or death in CKD patients (regardless of type 2 diabetes status), defined as a composite of a sustained decline in estimated glomerular filtration rate [eGFR] of ≥50%, onset of end-stage kidney disease [ESKD], or cardiovascular [CV] or renal death. Secondary endpoints included time to the first occurrence of a renal composite event (sustained eGFR decline ≥50%, ESKD, or renal death), a composite of CV death or hospitalization for heart failure (hHF), and time to all-cause death.

Data show that Forxiga has a statistically and clinically significant effect on the primary composite endpoint: in patients with stage 2–4 CKD and elevated urinary protein excretion (with or without type 2 diabetes mellitus), when added to standard of care, compared with placebo,In the Forxiga treatment group, the relative risk of worsening renal function and cardiovascular (CV) or renal death was significantly reduced by 39% (p < 0.0001), with an absolute risk reduction (ARR) of 5.3%.Results were consistent in patients with and without type 2 diabetes mellitus.

Additionally, the study also met all secondary endpoints, including compared with the placebo group,All-cause mortality was significantly reduced by 31% in the Forxiga group (ARR = 2.1%, p = 0.0035). In this study, the safety and tolerability of Forxiga were consistent with its known safety profile. Fewer serious adverse events occurred in the Forxiga group compared with the placebo group (29.5% vs. 33.9%, respectively). No diabetic ketoacidosis was reported in the Forxiga group, whereas 2 patients in the placebo group experienced it.

Based on the results of this study,Forxiga is the first drug to significantly prolong survival in a renal outcomes trial in CKD patients with and without type 2 diabetes.

Chronic kidney disease (CKD) is a severe progressive disease characterized by a decline in kidney function. It is estimated that nearly 840 million people worldwide are affected, many of whom remain undiagnosed. The most common causes of CKD are diabetes (38%), hypertension (26%), and glomerulonephritis (kidney inflammation, 16%). CKD is associated with significant morbidity and an increased risk of cardiovascular (CV) events, such as heart failure (HF) and premature death. In its most severe form, end-stage kidney disease (ESKD), kidney damage and functional decline have progressed to a stage requiring dialysis or kidney transplantation. Most patients with CKD die from cardiovascular causes before progressing to ESKD.

Forxiga is a first-in-class, once-daily oral selective sodium-glucose cotransporter 2 (SGLT2) inhibitor. It exerts a glucose-lowering effect independently of insulin by selectively inhibiting SGLT2 in the kidneys, thereby helping patients excrete excess glucose in the urine. In addition to lowering blood glucose, the drug offers additional benefits of weight loss and blood pressure reduction.

As science continues to uncover the potential connections between the heart, kidneys, and pancreas, research on Forxiga is expanding from cardiorenal effects to prevention and organ protection. For the heart, kidneys, and pancreas, damage to one organ can lead to failure in the others—ultimately driving the leading causes of death worldwide, including type 2 diabetes (T2D), heart failure (HF), and chronic kidney disease (CKD).

To date, Forxiga has been approved for multiple indications, which vary by country: (1) as monotherapy and as part of combination therapy, adjunct to diet and exercise, to improve glycemic control in patients with type 2 diabetes mellitus. (2) to reduce the risk of hospitalization for heart failure in patients with type 2 diabetes mellitus and established cardiovascular disease or multiple cardiovascular risk factors. (3) to reduce the risk of cardiovascular (CV) death and hospitalization for heart failure in adult patients with heart failure with reduced ejection fraction (HFrEF) (with or without type 2 diabetes mellitus). (4) as an oral adjunct to insulin to improve glycemic control in adult patients with type 1 diabetes mellitus (T1D) who are receiving insulin therapy but have inadequate glycemic control and a body mass index (BMI) ≥27 kg/m² (overweight or obese). (5) to reduce the risk of sustained decline in estimated glomerular filtration rate (eGFR), end-stage kidney disease (ESKD), cardiovascular (CV) death, and hospitalization for heart failure (hHF) in adult patients with chronic kidney disease (CKD) at risk of disease progression; this indication covers patients with or without type 2 diabetes mellitus (T2D).

DapaCare is a robust clinical trial program designed to evaluate the potential cardiovascular, renal, and organ-protective benefits of Farxiga. The program encompasses 35 completed and ongoing Phase IIb/III trials, involving over 35,000 patients and more than 2.5 million patient-years of experience. Currently, Farxiga is being evaluated in the Phase III DELIVER trial for the treatment of patients with heart failure with preserved ejection fraction (HFpEF). Additionally, Farxiga is also being assessed in the Phase III DAPA-MI trial to reduce the risk of hospitalization for heart failure (hHF) or cardiovascular (CV) death in adult patients without type 2 diabetes following an acute myocardial infarction (MI) or heart attack. (Bioon.com)