Filspari Drug Information

Immunoglobulin

A Nephropathy The effect of FILSPARI on proteinuria and kidney function (estimated glomerular filtration rate, eGFR) was assessed in a randomized, double-blind, active-controlled, multicenter, global study (PROTECT, NCT03762850 ) in adults with biopsy-proven primary IgAN, eGFR ≥30 mL/min/1.73 m 2, and total urine protein ≥1.0 g/day on a stable dose of maximally-tolerated RAS inhibitor treatment. Patients with chronic kidney disease due to another condition in addition to IgAN or those who had been recently treated with systemic immunosuppressants were excluded. Patients were randomized (1:1) to either FILSPARI (400 mg once daily following 200 mg once daily for 14 days) or irbesartan (300 mg once daily following 150 mg once daily for 14 days). Rescue immunosuppressive treatment could be initiated per investigator discretion during the trial.

Concomitant use of sodium-glucose cotransporter-2 (SGLT2) inhibitors, other RAS inhibitors, and aldosterone blockers were prohibited. The primary efficacy endpoint for the interim analysis was the change from baseline in urine protein/creatinine ratio (UPCR) at Week 36 based on the first 281 randomized patients who had reached the Week 36 visit. The key secondary efficacy endpoint for the final analysis was the rate of change in eGFR over a 110-week period following initiation of randomized therapy.

The 404 patients who enrolled and received study medication had a mean age of 46 years (range 18 to 76 years); 70% were male, 67% White, 28% Asian, and 1% Black or African American. Approximately 78% had a history of hypertension, 11% had diabetes or impaired fasting glucose, and 56% had hematuria based on urine dipstick. At baseline, the mean eGFR was 57 mL/min/1.73 m 2, the geometric mean UPCR was 1.2 g/g, and 49 (12%) patients had proteinuria >3.5 g/24 hours.

Urine Protein/Creatinine Ratio (UPCR) The trial met the prespecified primary endpoint of relative change from baseline in UPCR at Week 36 based on an interim analysis of 281 randomized patients who had reached the Week 36 visit. The interim analysis showed a 45% decrease in UPCR at Week 36 relative to baseline for patients treated with FILSPARI compared to a 15% decrease for patients treated with irbesartan resulting in a 35% reduction in the ratio of mean UPCR (95% CI: 23% to 45% reduction; p<0.0001). In the final analysis of 404 randomized patients, the treatment effects in UPCR observed at Week 36 and Week 110 were consistent with the results obtained at the interim analysis. The mean percent change from baseline over the course of the double-blind period is displayed in Figure 1. Figure 1: Geometric Mean Percent Change from Baseline in Urine Protein-to-Creatinine Ratio by Visit through Week 110 (PROTECT, FAS) Adjusted GMPC of UPCR was based on MMRM stratified by screening eGFR and total urine protein excretion.

MMRM analysis includes UPCR data during the double-blind period up to Week 110 regardless of treatment discontinuation or immunosuppressive therapy initiation. Missing data were imputed using multiple imputation under assumptions of missing at random and missing not at random depending on the patient’s intercurrent event status. Baseline was defined as the last non-missing observation on or prior to the start of dosing.

Counts in axis table represent number of subjects with observed UPCR data by visit and treatment group. BL=baseline; CI=confidence interval; FAS=full analysis set; GMPC=geometric mean percent change; LS=least squares; MMRM=mixed-model repeated measures; N= number of subjects with available data at the time of analysis; UPCR=urine protein/creatinine ratio. Estimated Glomerular Filtration Rate (eGFR) In the final analysis of 404 randomized patients, FILSPARI reduced the rate of decline in kidney function from baseline to Week 110 compared to irbesartan.

The mean eGFR slope from baseline to Week 110 was -3.0 mL/min/1.73 m 2 per year for FILSPARI and -4.2 mL/min/1.73 m 2 per year for irbesartan, corresponding to a treatment effect of 1.2 mL/min/1.73 m 2 per year (95 %CI: 0.2 to 2.1; p=0.0168). The mean change from baseline in eGFR during the double-blind period is shown in Figure 2. The treatment effect on the rate of change in eGFR through Week 110 was generally consistent across key subgroups, including key demographic (such as age, sex, race, ethnicity, and region) and baseline disease (such as baseline BMI and baseline proteinuria) characteristics. The treatment benefit with FILSPARI on the rate of change in eGFR through Week 110 was not evident in patients with an eGFR ≥90 mL/min/1.73 m 2 ; however, there was a small number of patients in this subgroup. Figure 2: Absolute Change in eGFR (mL/min/1.73 m 2 ) by Visit (FAS) *eGFR was calculated using the CKD-EPI equation.

Baseline was defined as the last non-missing observation on or prior to the start of dosing. The analysis includes eGFR data during the double-blind period up to Week 110 regardless of treatment discontinuation or immunosuppressive therapy initiation. Rescue immunosuppressive treatment for IgAN was initiated in 7 (3%) and 18 (9%) patients in the FILSPARI and irbesartan group respectively.

BL=baseline; CI=confidence interval; CKD-EPI=Chronic Kidney Disease Epidemiology Collaboration; eGFR=estimated glomerular filtration rate; FAS=full analysis set; IgAN=immunoglobulin A nephropathy; LS=least squares; N=number of subjects with available data at the time of analysis. Figure 1 Figure 2

Focal Segmental Glomerulosclerosis

The efficacy of FILSPARI in reducing proteinuria in patients 8 years and older with FSGS was assessed in the randomized, double-blind, active-controlled portion of a multicenter, global trial (DUPLEX, NCT03493685 ). DUPLEX randomized (1:1) 371 adult and pediatric patients 9 years of age and older with biopsy-proven FSGS or a genetic mutation known to cause FSGS, UPCR ≥1.5 g/g, and an eGFR ≥30 mL/min/1.73 m 2 to FILSPARI or irbesartan for 108 weeks. Genetic testing for mutations known to cause FSGS was not routinely obtained at study entry. The study excluded patients with FSGS secondary to another condition and kidney transplant recipients.

Subjects taking RAAS inhibitors at screening were required to complete a 2-week washout before randomization. Dosing was weight-based: patients weighing >50 kg received sparsentan 400 mg or irbesartan 150 mg once daily for 14 days; thereafter, the doses were titrated up to 800 mg and 300 mg once daily, respectively. For patients weighing ≤50 kg, sparsentan or irbesartan was initiated at 200 mg or 75 mg once daily, respectively, for 14 days then titrated up to 400 mg or 150 mg once daily, respectively.

Patients who had received rituximab, cyclophosphamide, or abatacept within 3 months before screening were excluded; other chronic immunosuppression (steroids, calcineurin inhibitors, mycophenolate mofetil, and azathioprine) had to be stable for at least one month. Concomitant use of RAAS inhibitors, endothelin system inhibitors, and potassium-sparing diuretics were prohibited. The primary efficacy endpoint at the final analysis was the rate of change in eGFR from baseline to Week 108. At baseline, the mean age of trial participants was 42 years (range 9 to 75 years); 54% were male; 73% were White, 13% Asian, 7% Black or African American, and 7% were other, multiple or unknown.

The trial population included 35 pediatric patients aged 9 to <18 years of age (mean age 14 years; 16 randomized to FILSPARI and 19 to irbesartan). At baseline, the mean eGFR was approximately 63 mL/min/1.73 m 2, and the geometric mean UPCR was approximately 3.1 g/g in both treatment groups. The primary efficacy endpoint at the final analysis was not statistically significant. In the overall DUPLEX population, the adjusted mean change from baseline to Week 108 in eGFR was -14.3 mL/min/1.73 m 2 in patients randomized to FILSPARI and -13.3 mL/min/1.73 m 2 in patients randomized to irbesartan.

Compared to irbesartan, the difference in the adjusted mean change from baseline to Week 108 in eGFR was -1.0 mL/min/1.73 m 2 (95% CI: -4.9, 2.8). The estimated mean change from baseline in eGFR up to Week 108 in the overall DUPLEX population is shown in Figure 3 below. Figure 3: Absolute Change in eGFR (mL/min/1.73 m 2 ) by Visit (Overall DUPLEX Population) Missing data were handled using multiple imputation. Patients who had initiated renal replacement therapy or died were sampled from the worst 5% of the observed eGFR data.

Changes from baseline in eGFR were analyzed using the primary mixed models repeated analysis model including treatment, baseline eGFR, visit weeks, stratification factors, interaction of visit weeks and treatment as factors. BL = baseline; CI = confidence interval; eGFR = estimated glomerular filtration rate; LS = least squares. In the overall population, the percent UPCR reduction from baseline to Week 108 was 46% in patients randomized to FILSPARI and 30% in patients randomized to irbesartan, resulting in a 22% (95% CI: 2%, 38%) UPCR reduction from baseline to Week 108 for patients randomized to FILSPARI compared to patients randomized to irbesartan.

At the end of the trial, all patients discontinued study drug at Week 108 and restarted standard of care treatment including RAAS inhibitors (other than irbesartan). There was no difference between treatment arms in the change in eGFR from baseline to Week 112 (i.e., four weeks after discontinuing randomized treatment) or percent reduction in UPCR from baseline to Week 112. Given sparsentan's mechanism of action and because key drivers of disease progression may be different in patients with and without nephrotic syndrome, analyses were conducted in the two subgroups. Nephrotic syndrome was defined as (a) documentation of nephrotic syndrome in the medical history, or (b) the concurrent presence of proteinuria >3.5 g/24 hours (adults) or UPCR >2.0 g/g (pediatric patients <18 years of age), serum albumin <3.0 g/dL, and edema at baseline. Table 5 shows the findings for the percent UPCR reduction from baseline at Week 108 and the adjusted mean change from baseline in eGFR at Week 108 for the overall population, patients without nephrotic syndrome, and patients with neprotic syndrome.

In the subgroup of patients without nephrotic syndrome, the percent UPCR reduction at Week 108 from baseline was 48% in patients randomized to FILSPARI compared to 27% in patients randomized to irbesartan. Compared to irbesartan, patients randomized to FILSPARI had a 29% (95% CI: 9%, 44%) reduction in the ratio of the mean UPCR at Week 108 from baseline. In contrast, there was no difference between treatment arms in UPCR reduction from baseline to Week 108 in the subgroup of patients with nephrotic syndrome.

Table 5: Changes from Baseline to Week 108 in UPCR and eGFR Missing data were handled using multiple imputation. Patients who had initiated renal replacement therapy or died were sampled from the worst 5% of the observed data. 1 Percent reduction in UPCR was obtained by nonlinear conversion of the adjusted mean log ratio of UPCR with baseline. 2 FILSPARI was compared with irbesartan based on the difference in the adjusted mean log ratio of UPCR at Week 108 with baseline. The percent reduction was then obtained using similar nonlinear conversion (in 1) on the mean differences in the log ratio of UPCR at Week 108 with baseline. 3 Adjusted mean change from baseline in eGFR is obtained from the mixed model repeated measures analysis.

The comparison between FILSPARI with irbesartan was based on the difference in adjusted mean change in eGFR at Week 108 with baseline on the absolute scale. *Nephrotic syndrome was defined as (a) documentation of nephrotic syndrome in the medical history, or (b) the concurrent presence of proteinuria >3.5 g/24 hours (adults) or UPCR >2.0 g/g (pediatric patients <18 years of age), serum albumin <3.0 g/dL, and edema at baseline. Patients without nephrotic syndrome did not meet both criteria (a) and (b). CI= confidence interval; eGFR = estimated glomerular filtration rate; % = percent; UPCR = urine protein to creatine ratio. Overall Population Without Nephrotic Syndrome* Nephrotic Syndrome* FILSPARI Irbesertan FILSPARI Irbesertan FILSPARI Irbesertan N 184 187 129 125 55 62 Percent Reduction in UPCR at Week 108 relative to baseline 1 46% 30% 48% 27% 39% 37% FILSPARI vs Irbesartan: Percent Reduction in UPCR at Week 108 2 (95% CI) 22% (2%, 38%) 29% (9%, 44%) 3% (-54%, 39%) Adjusted Mean Change in eGFR (mL/min/1.73 m 2 ) at Week 108 from baseline 3 -14.3 -13.3 -11.3 -12.4 -21.3 -

FILSPARI vs Irbesartan: Difference in Adjusted Mean Change in eGFR (mL/min/1.73 m2)

at Week 108 from baseline 3 (95% CI) -1.0 (-4.9, 2.8) 1.1 (-2.6, 4.8) -6.2 (-15.2, 2.9) The percent change from baseline in UPCR in the subgroup without nephrotic syndrome over the course of the double-blind period is displayed in Figure 4. Figure 4: Percent Change from Baseline in UPCR by Visit in the Subgroup Population Without Nephrotic Syndrome in DUPLEX (FAS) Missing data were handled using multiple imputation. Patients who had initiated renal replacement therapy or died were sampled from the worst 5% of the observed proteinuria data. Changes from baseline in log UPCR were analyzed using the mixed models repeated model including treatment, baseline logarithm of UPCR, visit weeks, stratification factors, interaction of visit weeks and treatment as factors,. BL = baseline; CI = confidence interval; FAS = full analysis set; LS = least squares; UPCR = urine protein to creatinine ratio.

The treatment effect on the percent reduction in UPCR at Week 108 relative to baseline was generally consistent across key subgroups defined by age, sex, race, and ethnicity. Figure 3 Figure 4