Sparsentan and the Expanding Landscape of IgA Nephropathy Treatment

IgA nephropathy is the most common glomerular disease worldwide, with well-recognized geographic and racial/ethnic differences in prevalence and disease severity. The spectrum of disease progression is also broad, but IgA nephropathy generally follows a protracted course, with a median time to kidney failure reported to be >25 years.1 The slow rate of progression to recognized "hard end points" of halving of eGFR, kidney failure (dialysis or transplantation), or death poses challenges for drug development as such trials require lengthy follow-up to accumulate sufficient outcome events. In 2016, the Kidney Health Initiative initiated a project to identify end points that could be used as the basis for drug approval for IgA nephropathy and specifically explored whether proteinuria reduction could be used as a surrogate end point. On the basis of US Food and Drug Administration's general considerations for surrogate end points and after careful review of key published clinical trials in IgA nephropathy available at the time, the Kidney Health Initiative workgroup concluded that proteinuria reduction could be considered a reasonably likely surrogate end point in IgA nephropathy.2 In the United States, a reasonably likely surrogate end point may be used for drug licensing on an accelerated pathway that requires postmarketing trials to confirm demonstrable benefit on hard end points before full approval. In parallel, numerous advances improved understanding of the pathogenesis of IgA nephropathy, notably with respect to the intestinal mucosa–kidney axis.3 These important developments collectively led to an explosion of clinical research in IgA nephropathy. Over 25 clinical trials are ongoing worldwide, testing agents targeting inflammatory pathways, complement activation, immune system regulation, and mucosal immunity.4 In the past 2 years, the results from four large randomized, controlled clinical trials have been published: the Therapeutic Effects of Steroids in IgA Nephropathy Global (TESTING) study using methylprednisolone,5 the NefIgArd study using a gastrointestinal mucosa targeted-release formulation of budesonide (Nefecon),6 the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) prespecified IgA nephropathy substudy using dapagliflozin,7 and the recent Study of the Effect and Safety of Sparsentan in the Treatment of Patients With IgA Nephropathy (PROTECT) using sparsentan8 (Table 1). We will briefly review these studies and provide a perspective on sparsentan. Table 1 - Summary of recent therapeutic studies in IgA nephropathy Trial Immunomodulatory Nonimmunomodulatory MethylprednisoloneTESTINGa BudesonideNefIgArd (Part A) DapagliflozinDAPA-CKD-IgA TESTINGa SparsentanPROTECT(Interim Analysis) N 503 199b 270 281 Intervention/control Methylprednisolone/placebo Targeted-release budesonide/placebo Dapagliflozin/placebo Sparsentan/irbesartan RAAS blockade, % 99.6 97.5 100 100 Primary end point Composite of 40% decline in eGFR, kidney failure,c or death due to kidney disease UPCR at 9 mo. Key secondary: eGFR and UACR at 9 mo and eGFR at 12 mo Composite of 50% decline in eGFR, kidney failure,c or death due to kidney or CVD Relative change from baseline in UPCR at week 36 Inclusion criteria eGFR 20–120, proteinuria ≥1 g/d eGFR 35–90, proteinuria ≥1 g/d or UPCR ≥0.8 g/g eGFR 25–75, UACR 0.2–0.5 g/g eGFR ≥30 and proteinuria ≥1 g/d Key exclusion criteria Strong indication or contraindication to glucocorticoids Immunotherapy within the previous 12 mo Immunotherapy within the previous 6 mo >25% cellular crescents, immunotherapy within the previous 3 mo, major hepatic, CVD Follow-up Mean 50 mo Prespecified analysis after 9-mo treatment and 3-mo follow-up Median 25 mo Prespecified interim analysis at 9 mo Patient population Age, yr Mean 38 Median 45 Mean 51 Mean 46 Sex, % women 39 32.2 32.6 31 eGFR Mean 61.5 Median 55 Mean 43.8 Mean 57 Proteinuria at baseline Mean 2.46 g/d Median UPCR 1.26 g/g Median UACR 0.9 g/g Mean UPCR 1.2 g/g Race/ethnicity 95% Asian or Southeast Asian 86% White, 12% Asian 40% White, 59% Asian 67% White, 29% Asian Effect estimate on primary end point HR, 0.53 (95% CI, 0.39 to 0.72); P < 0.001; annual event rate difference, −4.8% per year (95% CI, −8.0% to −1.6%) 48% (36%–58%); P < 0.0001 difference in percent reduction of UPCRd HR, 0.29 (95% CI, 0.12 to 0.73) composite outcomeHR, 0.24 (95% CI, 0.09 to 0.65; P = 0.002) kidney outcome 41% relative reduction in UPCR P < 0.0001OR complete remission 3.1 (95% CI, 1.6 to 5.8; P = 0.0005) Adverse events Hospitalizations, serious infectionse 9.3% versus 1% discontinued treatment. Similar incidence of infections in the two groups Fewer serious adverse events with dapagliflozin, and no new safety findings in this population REMS monitoring required for hepatotoxicity and embryo fetal toxicity Regulatory approval Not applicable Accelerated approval Approved for CKD Accelerated approval Planned confirmatory trial status Not applicable Ongoing follow-up study evaluating the effect on hard composite end point at 104 wk Not applicable Ongoing blinded trial evaluating the effect on hard composite end point at 110 wk 30-d WAC in the US ≤$89f $14,160 $532 $9900 eGFR reported in eGFR in ml/min per 1.73 m2. RAAS, renin-angiotensin-aldosterone system; UPCR, urine protein-to-creatinine ratio; UACR, urine albumin-to-creatinine ratio; CVD, cardiovascular disease; HR, hazard ratio; CI, confidence interval; OR, odds ratio; REMS, risk evaluation and mitigation system; WAC, wholesaler acquisition cost, or manufacturer's published price to wholesaler, US.aDepicts studies on the basis of hard end points (40% or 50% reduction in GFR, kidney failure, or death).bThree-hundred and six participants randomized, part A analysis reported analysis on 199 participants.cDialysis or kidney transplant.dBenefit of budesonide was not observed among patients with baseline urine protein-to-creatinine ratio <1.5 g/g.eExcess serious infections, including death, in the full-dose methylprednisolone rather than the reduced dose regimen.fBased on max dose of 32 mg/d for first 2 months. The previous Supportive Versus Immunosuppressive Therapy for the Treatment Of Progressive IgA Nephropathy (STOP-IgAN) nephropathy study demonstrated that diligent nonimmunosuppressive therapy is efficacious in reducing proteinuria to <0.75g/d in one third of patients.9 Addition of immunosuppression with glucocorticoids alone or glucocorticoids and azathioprine was associated with improved likelihood of complete remission of proteinuria but not in reducing GFR decline. Against this backdrop, the four recent clinical trials evaluated efficacy and risks of two immunomodulatory and two nonimmunomodulatory approaches. The TESTING study demonstrated that methylprednisolone significantly reduced the risk of a 40% reduction in eGFR, kidney failure, or death compared with supportive therapy alone. However, this study also provided a stark reminder of the serious infectious risks of high- or even moderate-dose glucocorticoids (7% versus 1%).5 NefIgArd demonstrated that targeted-release budesonide therapy significantly reduced proteinuria compared with placebo. The rationale for this budesonide formulation rests on the concept that intestinal mucosal immunity contributes to pathogenesis of IgA nephropathy. However, aside from overt inflammatory bowel disease, no reliable assessments currently exist to identify patients for whom this particular mechanism is important. The NefIgArd trial is still ongoing as a blinded observational phase with supportive care only (Part B) to evaluate the sustained effect of prior targeted-release budesonide treatment on an eGFR-based end point as is required for agents approved on the accelerated pathway.6 Without a head-to-head study, the relative benefit and risk profile of targeted-release budesonide compared with usual corticosteroids remains unanswered. In the nonimmunomodulation camp, two relatively new agents have emerged: the sodium-glucose cotransporter-2 inhibitors (SGLT2i) dapagliflozin and sparsentan. The SGLT2i data are very compelling on the basis of a large population and on hard end points of the composite of 40% reduction of GFR, kidney failure, or death. SGLT2i are now well documented to provide significant benefit to patients with proteinuria and CKD, including patients with IgA nephropathy.7 Furthermore, the reduction in proteinuria is comparable with that of other medications discussed here, with a favorable safety profile. Sparsentan is a dual endothelin receptor antagonist and angiotensin receptor blocker. This agent recently obtained US Food and Drug Administration accelerated pathway approval with required confirmatory postmarketing studies. The PROTECT study assessed the effect of sparsentan on proteinuria reduction in a randomized, double-blind, active-controlled study in 281 adults with biopsy-proven IgA nephropathy, eGFR ≥30 ml/min per 1.73 m2, and proteinuria ≥1.0 g/d receiving maximized renin-angiotensin-aldosterone system (RAAS) blockade.8 Patients were randomized to either sparsentan (400 mg once daily) or irbesartan (300 mg once daily). SGLT2i use was prohibited. The primary end point was the relative change from baseline in urine protein-to-creatinine ratio at week 36. The geometric mean of urine protein-to-creatinine ratio decreased from 1.2 g/g to 0.7 (−45% [−51% to −38%]) and to 1.0 (−15% [−24% to −4%]) in the sparsentan and irbesartan groups, respectively. In the reported phase of PROTECT, increases in aminotransferases to more than three times the upper limit of normal occurred in 2% of each group and were asymptomatic and reversible. Sparsentan is currently available through a Risk Evaluation and Mitigation Systems program because of observed hepatoxicity with some endothelin receptor antagonists. This program requires documenting serum aminotransferases and total bilirubin before treatment, monthly for 12 months, and then every 3 months thereafter in addition to pregnancy testing monthly during treatment. The double-blind treatment phase of PROTECT is ongoing to further evaluate the effect of sparsentan compared with irbesartan on the hard end point of eGFR, kidney failure, or death. Multiple studies have identified the risk factors of progression of IgA nephropathy.10 Although predictive outcome models may identify those at risk, they do not help determine which patients may benefit from immunomodulation. IgA nephropathy is clearly not uniform across all patients with respect to mechanistic drivers of disease, risk of progression, and potential response to a specific therapy. Going forward, the development of clinical and/or biomarker-based models is needed to help predict which patients need immunotherapy in addition to maximized supportive therapy with RAAS or RAAS+endothelin blockade and/or SGLT2 inhibition. Identifying individuals for whom therapy targeting mucosal immunity is likely to be beneficial is similarly important as is identifying those who may need other systemic immunotherapy. The need for better predictive models of individualized therapy is highlighted by potential risks associated with the medications and their substantial costs. The current studies, which have evaluated therapies with very different mechanisms of action, raise important questions regarding what should constitute the comparator group in future trials in IgA nephropathy. In our opinion, the demonstrated benefits of nonimmunosuppressive therapy alone do not support corticosteroids as the standard against which all future investigational agents should be compared. Conversely, benefits of SGLT2i seem applicable to multiple underlying causes of kidney disease, are rapidly gaining use in clinical practice, and are increasingly allowed in currently ongoing clinical trials in IgA nephropathy. As such, their use may be de facto becoming part of "standard-of-care supportive therapy." The benefit and safety of combined use of SGLT2i and dual endothelin–angiotensin blockade is currently under investigation (NCT05856760) and may become the basis of maximized supportive therapy in IgA nephropathy even when immunotherapy is likely warranted. An important consideration of the presented studies is the lack of histologic data, specifically the mesangial hypercellularity (M), endocapillary proliferation (E), segmental glomerulosclerosis or adhesions (S), tubular atrophy and interstitial fibrosis (T), and crescent (C) (MEST-C) scoring. Whether the benefit of a therapeutic intervention may differ depending on the degree of active inflammation versus scarring is therefore unknown, which may be particularly important for immunomodulatory therapies. Future studies may benefit from inclusion of MEST-C scoring when available within a reasonable period of time before trial enrollment. Relevantly, patients with crescentic IgA nephropathy or with exposure to immunotherapy were excluded from the current studies. Importantly, as both the sparsentan and budesonide trials leveraged the accelerated approval pathway on the basis of a reasonably likely surrogate end point (proteinuria reduction), ongoing phases of these trials6,8 will test whether these agents are effective in reducing hard end points of kidney disease. In addition to direct assessment of efficacy for these agents themselves, final results of these trials will support or refute the hypothesis that a partial reduction in proteinuria can indeed be used as surrogate end point in IgA nephropathy.