How Do DEARAs Work?

Dual endothelin angiotensin receptor antagonists (DEARAs) are a novel class of drugs approved by the FDA in February, 2023 to reduce proteinuria in adults with primary immunoglobulin A nephropathy (IgAN), also known as Berger disease. Sparsentan, (brand name Filspari), is the first and currently the only drug to be approved in this class, and the first non-immunosuppressive therapy for reducing proteinuria in IgAN.

Immunoglobulin A nephropathy is a progressive kidney disease caused by a buildup of IgA deposits that inflame and scar the kidney. IgA is an antibody produced by the body to fight infections. IgA deposits in kidney damage the glomeruli, the tiny functioning kidney units with looping blood vessels that filter wastes, leading to leakage of blood and protein in the urine and progressive loss of kidney function.

Dual endothelin angiotensin receptor antagonists help reduce the leakage of protein in urine by blocking the activity of endothelin-1 and angiotensin-II. Endothelin-1 is a peptide secreted by endothelial cells that form the inner lining of blood vessels, to make blood vessels constrict. Angiotensin II is a peptide hormone that increases blood pressure and induces water and sodium retention in the kidneys.

Endothelin-1 and angiotensin-II are believed to contribute to disease progression in IgA nephropathy by stimulating endothelin 1A receptors (ETAR) and angiotensin II type 1 (AT1R) receptors respectively, in the kidneys and vascular smooth muscles. DEARAs selectively block endothelin 1A receptors (ETAR) and angiotensin II type 1 (AT1R) receptors and prevent their stimulation.

Sparsentan, the only FDA-approved DEARA was developed by merging the structural elements of irbesartan, an angiotensin II antagonist, and biphenylsulfonamide, an endothelin-1 antagonist. Sparsentan was initially developed to treat hypertension, however, it was shown to be effective in reducing proteinuria in IgA nephropathy and was granted accelerated approval by the FDA.

Dual endothelin angiotensin receptor antagonists are oral tablets approved by the FDA to reduce proteinuria in adults with primary immunoglobulin A nephropathy who are at risk for rapid disease progression, generally those who have a urine protein-to-creatinine ratio of 1.5 g/g or higher.

Side effects of endothelin dual angiotensin receptor antagonists may include the following:

• Low blood pressure (hypotension)
• Drop in blood pressure when standing up from sitting or lying down (orthostatic hypotension)
• Swelling of extremities (peripheral edema)
• High blood potassium (hyperkalemia)
• Dizziness
• Anemia
• Acute kidney injury
• Elevation of liver enzymes (transaminases)

Information contained herein is not intended to cover all possible side effects, precautions, warnings, drug interactions, allergic reactions, or adverse effects. Check with your doctor or pharmacist to make sure these drugs do not cause any harm when you take them along with other medicines. Never stop taking your medication and never change your dose or frequency without consulting your doctor.

Generic and brand names of dual endothelin angiotensin receptor antagonists (DEARAs) include:

• sparsentan
• Filspari