Esparsentan Breakthrough Transforms Treatment of IgA Nephropathy

Until recently, encountering a patient with IgA nephropathy in a nephrology clinic meant being unable to provide them with a specific treatment for their disease and having to rely on “supportive” medications and lifestyle recommendations: a low-salt diet, control of cardiovascular risk factors, and exercise.

This rare autoimmune disease, which affects very young people and can lead to chronic kidney failure requiring dialysis or a kidney transplant in just a few years, lacked a specific medication capable of influencing its progression and pathophysiology.

Antihypertensive drugs, specifically inhibitors of the renin-angiotensin-aldosterone system (RAAS), were used to control proteinuria, a key marker of kidney damage and prognosis in this disease. More recently, antidiabetic drugs, specifically sodium-glucose cotransporter 2 (SGLT2) inhibitors, were added to the treatment regimen.

For IgA nephropathy patients in whom this support was ineffective and the disease progressed rapidly, immunosuppressants were used, “with trials showing little evidence for slowing disease progression and significant adverse effects,” recalled Dr. María Ángeles Goicoechea , head of the Nephrology Department at the Gregorio Marañón University General Hospital, this past Monday.

Esparsentan has been shown in clinical trials to slow the decline in kidney function in patients with IgA nephropathy over two years compared to standard treatment

The approach to IgA nephropathy, which is estimated to affect more than 16,000 people in Spain, is set to change with the introduction of a new treatment into the national healthcare system. This treatment, developed specifically for this disease, is the first non-immunosuppressive drug approved in Europe for this indication, according to CSL, the biopharmaceutical company that develops and markets it. Called esparsentan (Filspari), it has demonstrated in clinical trials its ability to slow the decline in kidney function for two years compared to standard treatment.

“This is a clinical milestone for this disease,” Dr. Goicoechea stated during the drug’s presentation. “ We are delaying the need for dialysis , which is the primary goal for young people, for whom it represents a radical life change, in addition to lower hospital costs, fewer admissions, less emotional and work-related burden, and greater autonomy and quality of life.” It is, therefore, “capable of modifying the natural history of the disease,” she asserted.

What does the drug do for IgA nephropathy?

Patients living with this rare disease and the nephrologists who treat it face a key enemy: the silent way in which it can progress to its most severe stage. “It is the most frequent cause of needing renal replacement therapy in patients under 40 years of age,” noted Dr. Antolina Rodríguez Moreno , attending physician in the Nephrology Department at the San Carlos Clinical Hospital.

Only in one of its clinical forms, “which is not the most frequent,” can it be detected in adolescents, who arrive “with a respiratory infection and are urinating blood.” But, in general, IgA nephropathy progresses without symptoms, and “more than 60% of the patients we see in our clinic already have established kidney failure, and we are too late with treatments” laments the expert from the San Carlos University Hospital.

The progression of IgA nephropathy can be stabilized with supportive treatments and lifestyle changes, but in a significant proportion, none of this works. “One out of every four diagnoses ends up in end-stage chronic kidney disease within four or five years,” she pointed out.

In this condition, the most common of the primary or autoimmune glomerulopathies, immunoglobulin A (IgA) is produced inappropriately, leading to the disease. This antibody, which acts as the first line of defense against microorganisms in the mucous membranes, is not recognized by the immune system, which generates autoantibodies against this aberrant IgA. This causes the formation of immune complexes that eventually accumulate in the kidneys, leading to inflammation and chronic kidney damage. IgA nephropathy manifestations include proteinuria and hematuria in the urine, and progressive kidney failure.

What esparsentan does is combine an endothelin-A receptor antagonist (ETA) and an angiotensin II type 1 receptor blocker (AT1) with a “dual and unique” mechanism of action that “reduces intraglomerular pressure, inflammation, and fibrosis—the three key processes in the progression of IgA nephropathy ,” explained Dr. Goicoechea. Clinical trials have shown that it achieves a “very rapid and significant reduction in proteinuria, with almost a 50% decrease . “

Esparsentan “reduces intraglomerular pressure, inflammation and fibrosis, the three key processes in the progression of IgA nephropathy”

Not all diagnosed patients will be able to benefit from the new treatment. The indication, approved on February 25th by the Interministerial Commission on Prices of the National Health System (SNS), after reviewing the arguments presented by CSL following an initial rejection on December 25th, involves restrictions.

It is funded for adult patients who have biopsy-confirmed disease and are at high risk of disease progression with protein excretion greater than or equal to one gram per day and an estimated glomerular filtration rate greater than or equal to 30. Although the national registry of patients with this condition is not mandatory and, therefore, not all cases and data are recorded, the company believes that its drug could reach approximately 6,000 cases.

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