Nonimmunosuppressive Treatment Approved for Primary IgA Nephropathy

Elizabeth Marino;Shayne Sampognaro;

Nonimmunosuppressive Treatment Approved for Primary IgA Nephropathy

July 21, 2023

Elizabeth Marino
Shayne Sampognaro

Publication

Article

Drug Topics JournalDrug Topics May 2023

Volume 167

Issue 05

In February 2023, the FDA granted accelerated approval to sparsentan (Filspari), an oral, once-daily, nonimmunosuppressive medication to reduce proteinuria in patients with IgA nephropathy (IgAN) who are at risk for rapid disease progression.¹ Sparsentan is a dual antagonist of the endothelin type A and angiotensin II type 1 receptors, both of which are believed to play a role in IgAN pathogenesis.

Efficacy

Sparsentan received accelerated approval based on the interim results of the double-blind, randomized, active-control, phase 3 PROTECT trial (NCT03762850). The primary study outcome was the relative change in urine protein-to-creatinine ratio (UPCR) from baseline to week 36. Study participants were adults with primary IgAN on a maximized stable dose of a renin-angiotensin system inhibitor with proteinuria greater than or equal to 1.0 g/d, estimated glomerular filtration rate greater than or equal to 30 mL/min/1.73 m2, and blood pressure less than or equal to 150/100 mm Hg. Investigators excluded patients with chronic kidney disease, other glomerulopathies, hepatobiliary disease, transaminases greater than 2 times the upper limit of normal (ULN), and those treated with systemic immunosuppressants within 3 months.

Participants were randomly assigned to receive sparsentan 200 mg/d for 14 days, then 400 mg/d or irbesartan 150 mg/d for 14 days, then 300 mg/d. Interim study results were based on data from 281 participants with a mean baseline UPCR of 1.2 g/g. At 36 weeks, participants in the sparsentan group experienced a geometric mean reduction in proteinuria of 45% vs 15% with irbesartan (relative ratio, 0.65; 95% CI, 0.55-0.77).

Sparsentan has not been shown to slow progression of renal impairment. Continued FDA approval will depend on final results of PROTECT, expected to conclude in August 2023.

Safety

Sparsentan carries boxed warnings for hepatotoxicity and embryo-fetal toxicity. Levels of bilirubin and transaminases should be measured prior to initiation and monthly for the first 12 months, then every 3 months thereafter. If levels of aminotransferases are greater than 3 times the ULN, sparsentan therapy should be interrupted. Increased monitoring of enzymes, bilirubin, and international normalized ratio are recommended until laboratory values return to pretreatment levels and any symptoms resolve. Symptoms may include nausea, vomiting, fatigue, abdominal pain or tenderness (right upper quadrant), rash, fever, and elevated eosinophil count. In animal trials, sparsentan was shown to cause major birth defects. Patients must participate in the Filspari REMS program, with required pregnancy testing prior to treatment, during, and 1 month after medication discontinuation.

Common adverse reactions include hypotension, peripheral edema, hyperkalemia, and dizziness (each with ≥ 10% of participants). Other reported adverse events include anemia (5%), increased levels of aminotransferases (2.5%), and acute kidney injury (4%). Coadministration with angiotensin receptor blockers, endothelin receptor antagonists, or aliskiren is contraindicated. Sparsentan use should be avoided with concomitant strong cytochrome P450 34a inhibitors and inducers, as well as substantial substrates of P-glycoprotein and BCRP.

Dosing and Administration

Sparsentan is available in 200-mg and 400-mg oral tablets under the brand name Filspari. Before starting sparsentan, patients must discontinue use of renin-angiotensin-aldosterone system inhibitors to avoid potential adverse or toxic effects. Sparsentan should be initiated at 200 mg/d. After 14 days, the dose should be increased to 400 mg/d. If an interruption in therapy occurs, reinitiate sparsentan at 200 mg/d. Tablets should be swallowed whole with water before the morning or evening meal. Sparsentan should be avoided in patients with any hepatic impairment due to the potential risk of liver injury.