What are the functions and uses of Sparsentan?

Sparsentan is a single-molecule dual endothelin angiotensin receptor antagonist (DEARA) currently being studied for the treatment of focal segmental glomerulosclerosis (FSGS) and IgA nephropathy (IgAN).

Function and use

It is a single molecule that antagonizes endothelin type a receptor (ETaR) and angiotensin II type 1 receptor (AT1R). Reduces proteinuria in patients with IgA nephropathy by selectively blocking the action of two potent vasoconstrictor and mitogenic drugs, Ang II and endothelin 1 (ET-1), at their respective receptors.

On February 17, 2023, the US FDA accelerated the approval of sparsentan for marketing to reduce proteinuria in adult patients with primary immunoglobulin A nephropathy (IgAN) who are at risk of rapid disease progression. Under normal circumstances, the urine protein/creatinine ratio (UPCR) is ≥1.5g/g.

Recommended dosage

During initial treatment with sparsentan, 200 mg once daily is required. After 14 days, the dose should be increased to the recommended dose of 400 mg once a day according to the patient's tolerance. The patient should take the medication at approximately the same time every day. When reinitiating spaxentan therapy after an interruption, consideration should be given to titrating spaxentan starting at 200 mg once daily. After 14 days, increase to the recommended dose of 400 mg once daily.

clinical efficacy

Background: There is an unmet need for treatment of focal segmental glomerulosclerosis (FSGS). In an 8-week phase 2 trial, sparsentan, a dual endothelin-angiotensin receptor antagonist, reduced proteinuria in patients with FSGS. The efficacy and safety of long-term use of sparsentan in the treatment of FSGS are unknown.

Methods: In this phase 3 trial, patients aged 8 to 75 years with FSGS (no known secondary cause) were recruited and randomly assigned to receive sparsentan or irbesartan (active control) for 108 weeks. The surrogate efficacy endpoint evaluated in the prespecified interim analysis at 36 weeks was the FSGS partial response endpoint for proteinuria (defined as a urine protein to creatinine ratio of ≤1.5 [protein and creatinine in grams] and a >40% decrease in the ratio from baseline). The primary efficacy endpoint was estimated glomerular filtration rate (eGFR) slope at the time of final analysis. Change in eGFR from baseline to 4 weeks after the end of treatment (week 112) was a secondary endpoint.

Results: A total of 371 patients underwent randomization: 184 were assigned to receive sparsentan and 187 to receive irbesartan. At week 36, the percentage of patients with partial response to proteinuria was 42.0% in the sparsentan group and 26.0% in the irbesartan group, and this response was sustained for 108 weeks. At the final analysis at week 108, there were no significant between-group differences in eGFR slope; the between-group difference in total slope (day 1 to week 108) was 0.3 ml per minute per 1.73 m2 of body surface area per year (95% confidence interval [CI], -1.7 to 2.4), the between-group difference in the slope from weeks 6 to 108 (i.e., chronic slope) was 0.9 ml per minute per 1.73 square meters per year (95% CI, -1.3 to 3.0). The mean change in eGFR from baseline to week 112 was -10.4 ml per 1.73 m2 per minute with sparsentan and -12.1 ml per 1.73 m2 per minute with irbesartan (difference, 1.8 ml per 1.73 m2 per minute; 95% confidence interval, -1.4 to 4.9). Sparsentan and irbesartan had similar safety profiles, with similar rates of adverse events in both groups.

Conclusions: In patients with FSGS, there were no significant between-group differences in eGFR slope at 108 weeks, although albuminuria was reduced to a greater extent with sparsentan compared with irbesartan.

Pharmacokinetics

Population pharmacokinetic (PK) analysis was performed to characterize the PKs of sparsentan and to evaluate the impact of FSGS disease characteristics and concomitant medications as covariates on the PKs of sparsentan. Blood samples were collected from 236 healthy volunteers, 16 subjects with impaired liver function, and 194 patients with primary and hereditary FSGS who participated in nine studies ranging from Phase I to Phase III.

A total of 20 covariates were tested using univariate forward addition and stepwise backward elimination analyses, with significance levels of p<0.01 and p<0.001, respectively. Sparsentan PKs were described by a two-compartment model with first-order absorption and absorption lag times with proportional plus additive residuals (2 ng/mL). Due to CYP3A auto-induction, clearance is increased by 32% at steady state.

Covariates retained in the final model included formulation, cytochrome P450 (CYP) 3A4 inhibitor coadministration, sex, race, creatinine clearance, and serum alkaline phosphatase. The combination of moderate-dose and strong-dose CYP3A4 inhibitors increased the area under the concentration-time curve by 31.4% and 191.3%, respectively.

Population pharmacokinetic modeling of sparsentan suggests that dose adjustment may be necessary in patients taking both moderate and strong CYP3A4 inhibitors, but other covariates analyzed may not require dose adjustment.

Summary

Sparsentan is indicated for the reduction of proteinuria in adult patients with primary immunoglobulin A nephropathy (IgAN) who are at risk for rapid disease progression, usually with a urine protein to creatinine ratio (UPCR) ≥1.5g/g. It is recommended that patients strictly follow the doctor's instructions when taking medication and deal with it promptly if symptoms occur during medication.

Recommended related articles: