General Information

Filspari (sparsentan) is an endothelin and angiotensin II receptor antagonist.

Filspari is specifically indicated to reduce proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk of rapid disease progression, generally a urine protein-to-creatinine ratio (UPCR) ≥1.5 g/g.

Filspari is supplied as tablets for oral administration. Prior to initiating treatment, discontinue use of renin-angiotensin-aldosterone system (RAAS) inhibitors, endothelin receptor antagonists (ERAs), and aliskiren.

• Initiate treatment with Filspari  only after measuring aminotransferase levels and total bilirubin. Avoid initiation in patients with elevated aminotransferases (>3x ULN). Continue required monitoring monthly for the first 12 months after initiation or restarting following an interruption due to elevated transaminases, then every 3 months during treatment with Filspari.
• Initiate treatment with Filspari in patients who can become pregnant only after confirmation of a negative pregnancy test. Pregnancy tests are required monthly during treatment and one month after discontinuation of treatment with Filspari.

Recommended Dosage:

• Initiate treatment with Filspari  at 200 mg orally once daily. After 14 days, increase to the recommended dose of 400 mg once daily, as tolerated. 
• When resuming treatment with Filspari after an interruption, consider titration of Filspari, starting at 200 mg once daily. After 14 days, increase to the recommended dose of 400 mg once daily. 
• Instruct patient to swallow tablets whole with water prior to the morning or evening meal. Maintain the same dosing pattern in relationship to meals.
•  If a dose is missed, take the next dose at the regularly scheduled time. Do not take double or extra doses.

See drug prescribing label for dosage adjustment for aminotransferase elevations.

Mechanism of Action

Sparsentan is a single molecule with antagonism of the endothelin type A receptor (ETAR) and the angiotensin II type 1 receptor (AT1R). Sparsentan has high affinity for both the ETAR (Ki= 12.8 nM) and the AT1R (Ki=0.36 nM), and greater than 500-fold selectivity for these receptors over the endothelin type B and angiotensin II subtype 2 receptors. Endothelin-1 and angiotensin II are thought to contribute to the pathogenesis of IgAN via the ETAR and AT1R, respectively.

Side Effects

Side effects associated with the use of Filspari may include, but are not limited to, the following:

• peripheral edema
• hypotension (including orthostatic hypotension)
• dizziness
• hyperkalemia
• anemia

The Filspari comes with a Black Box Warning for hepatotoxicity and embryo-fetal toxicity. 

Some endothelin receptor antagonists have caused elevations of aminotransferases, hepatotoxicity, and liver failure. Measure liver aminotransferases and total bilirubin prior to initiation of treatment and ALT and AST monthly for 12 months, then every 3 months during treatment. Interrupt treatment and closely monitor patients developing aminotransferase elevations more than 3x Upper Limit of Normal (ULN). Based on animal data, Filspari can cause major birth defects if used during pregnancy. Pregnancy testing is required before, during, and after treatment. Patients who can become pregnant must use effective contraception prior to initiation of treatment, during treatment, and for one month after.

Clinical Trial Results

This indication is approved under accelerated approval based on reduction of proteinuria. It has not been established whether Filspari slows kidney function decline in patients with IgAN. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial.

The accelerated approval was based on clinically meaningful and statistically significant improvements in proteinuria compared to an active comparator in the pivotal and ongoing Phase 3 PROTECT Study, the largest head-to-head interventional study to date in IgAN. The PROTECT Study is a global, randomized, multicenter, double-blind, active-controlled clinical trial evaluating the safety and efficacy of 400 mg of Filspar, compared to 300 mg of irbesartan, in 404 patients ages 18 years and up with IgAN and persistent proteinuria despite maximal tolerated ACE or ARB therapy.

Topline interim results were based on the pre-specified, primary analyses set which showed that after 36 weeks of treatment, patients receiving Filspari achieved a mean reduction in proteinuria from baseline of 49.8%, compared to a mean reduction in proteinuria from baseline of 15.1% for irbesartan-treated patients. Per request from the FDA, the efficacy data contained in the FDA-approved label is a post-hoc sensitivity analysis that evaluates the first 281 randomized patients, a subset of the full trial population. The mean reduction in proteinuria from baseline in the post-hoc sensitivity analysis is 45% for Filspari versus 15% for the active control, irbesartan. Both the pre-specified and post-hoc sensitivity analyses have demonstrated that Filspari achieves a rapid and sustained reduction in proteinuria, with statistically significant and clinically meaningful improvement compared to the active comparator irbesartan.