Sparsentan (1) – Filspari®

• Clinical trials
  • For the benefit assessment, the pharmaceutical manufacturer has submitted analyses of the Phase III PROTECT trial. This was a multicentre, randomised, controlled, double-blind trial designed to investigate the safety and efficacy of sparsentan compared with irbesartan.

Adults with primary immunoglobulin A nephropathy (IgAN) with urinary protein excretion of ≥ 1.0 g/day (or a urinary protein-to-creatinine ratio of ≥ 0.75 g/g)

• Overall, there is a hint of a minor additional benefit of sparsentan for the treatment of adults with primary IgAN.
• mortality
  • Fatalities were recorded as part of the safety monitoring programme. A total of one death occurred in the comparator arm. No effect estimators were provided with the dossier. Given the number of events, no statistically significant difference between the treatment arms is assumed. However, a final assessment is not possible.
  • One death occurred among patients treated with irbesartan. However, the mortality data cannot be assessed due to the lack of effect estimates.
• Morbidity – Progression of kidney disease: End-stage renal disease (ESRD)
  • End-stage renal disease (ESRD) is defined in this study as the initiation of renal replacement therapy or a sustained eGFR < 15 ml/min/1.73 m². For the benefit assessment, the proportion of patients who reach confirmed ESRD by week 110 is used, and the time-to-event analysis is presented as a supplement.
  • No statistically significant differences were observed between the treatment arms for the endpoint of end-stage renal disease.
• Morbidity – progression of kidney disease: progression to CKD stage 4 or 5
  • The classification of CKD stages was based on eGFR/GFR using objective and internationally recognised KDIGO criteria. Individuals with CKD stage 4 have serious reductions in kidney function with a GFR of 15–29 ml/min/1.73 m². CKD stage 5 is defined as a GFR < 15 ml/min/1.73 m².
  • Progression to CKD stage 4 or 5 is considered clinically relevant. For the benefit assessment, the proportion of participants reaching CKD stage 4 or 5 by week 110 is used, and the time-to-event analysis is presented as a supplementary measure.
  • For the post-hoc endpoint of progression to CKD stage 4 or 5, no statistically significant difference was observed without adjustment for the randomisation strata. Following the oral hearing, the pharmaceutical manufacturer submitted the adjusted effect estimates. The analysis taking into account the randomisation strata is considered methodologically more appropriate and is therefore included in the benefit assessment.
  • For the endpoint ‘progression to CKD stage 4 or 5’, there is a statistically significant advantage in favour of sparsentan compared with irbesartan.
• Morbidity – change in renal function, measured by proteinuria
  • The primary endpoint of the study was the change in renal function, measured by proteinuria, which was operationalised, amongst other things, as the percentage change in the UP/C ratio from baseline to week 110. This endpoint represents a laboratory parameter with no direct relation to symptoms. Within the G-BA, there are differing views as to whether proteinuria constitutes a patient-relevant endpoint in its own right. As was also addressed in the commenting procedure, proteinuria represents a relevant parameter for guiding treatment in the present therapeutic indication. The pharmaceutical manufacturer has not provided any suitable studies to validate proteinuria as a surrogate for a patient-relevant endpoint. Furthermore, there are uncertainties regarding the imputation of missing values for this endpoint. However, as this is the primary endpoint of the study, it is presented here for the sake of completeness.
• quality of life
  • The quality of life data cannot be assessed. The endpoint ‘Kidney Disease Quality of Life 36-item short version’ (KDQOL-36) cannot be taken into account for the benefit assessment due to minor (< 70 %) response rates in the irbesartan treatment arm at all post-baseline measurement time points and due to response rates that differed significantly in some cases.
  • No evaluable data are available regarding quality of life.
• Side effects – Total adverse events (AEs)
  • AEs occurred in approximately 90% of patients in each study arm. The results are presented here only as supplementary information.
• Overall assessment
  • Results are available for the benefit assessment of sparsentan in the treatment of adults with primary IgAN from the randomised, double-blind PROTECT trial, in which sparsentan was compared with irbesartan.
  • One death occurred among patients treated with irbesartan. The mortality data cannot be assessed due to missing effect estimates.
  • In the morbidity endpoint category, regarding the progression of kidney disease for the endpoint of reaching CKD stage 4 or 5, there is a statistically significant advantage in favour of sparsentan compared with irbesartan, although this advantage is considered to be of a minor extent.
  • With regard to the quality of life endpoint category, the data cannot be assessed due to minor response rates.
  • In the ‘side effects’ endpoint category, too, no overall advantages or disadvantages of sparsentan over irbesartan can be identified.
  • In its overall assessment of the available results for patient-relevant endpoints, the G-BA classifies the extent of the additional benefit of sparsentan for the treatment of adults with primary IgAN, on the basis of the criteria set out in Section 5(8) in conjunction with Section 5(7), first sentence, points 1 to 4 of the AM-NutzenV are minor.
• Overall assessment
  • The potential for bias is assessed as high at both the study level and the endpoint level. This is attributable, amongst other things, to uncertainties regarding concomitant medication and follow-up therapies. With regard to follow-up therapies, there is particular uncertainty concerning those individuals who, following premature withdrawal from the study, had their previous treatment regimen discontinued.
  • Furthermore, it should be noted that patients in the control arm of the PROTECT study received monotherapy with an angiotensin receptor blocker (irbesartan). The use of irbesartan alone does not correspond to the currently recognised standard of care for the treatment of primary IgAN. Taking into account the statements made by clinical experts during the commenting procedure, patients with primary IgAN should receive an SGLT2 inhibitor (e.g. irbesartan) should also be prescribed an SGLT2 inhibitor (e.g. dapagliflozin).
  • Overall, the strength of the evidence is classified as ‘hint’ due to the uncertainties mentioned.

Courtesy translation only, please refer to the German original.