Sparsentan: the first and only non-immunosuppressive therapy for the reduction of proteinuria in IgA nephropathy

ABSTRACT

Introduction

IgA nephropathy is one of the most common forms of glomerular disease. Patients with persistent proteinuria are at increased risk of progression to kidney failure. There is a significant need for safe and effective therapies to lower proteinuria in these patients. Sparsentan is a non-immunosuppressive agent that acts as a dual angiotensin and endothelin receptor antagonist. It lowers proteinuria in experimental models of glomerular disease and in affected patients.

Areas covered

This review covers the immunological and non-immunological actions of sparsentan in glomerular disease. It reviews the clinical trials that evaluated the impact of the drug in pediatric and adult patients with IgA nephropathy. It places the use of sparsentan in an overall treatment paradigm for the full spectrum of patients with IgA nephropathy including nonspecific renoprotective agents such as inhibitors of the renin-angiotensin-aldosterone axis and SGLT2 transporter and immunosuppressive drugs. The review represents a search of the current literature about the effect of the drug on normal physiology and the pathogenesis of IgA nephropathy.

Expert opinion

The safety, tolerability, and therapeutic efficacy of sparsentan have been demonstrated in long-term studies of patients with primary glomerular diseases extending over 5 years. The evidence in support of a beneficial treatment effect of sparsentan is stronger in IgAN than in FSGS. It is anticipated that sparsentan will supplant the use of ACEI or ARB as the first-line therapy to reduce proteinuria prior to the implementation of immunosuppressive agents in patients with IgA nephropathy. It may be combined with other renoprotective drugs like SGLT2 inhibitors. Practice guidelines are needed to promote safe and effective use of this new drug by nephrologists caring for patients with IgAN in all clinical settings.

KEYWORDS:

• Sparsentan
• IgA nephropathy
• proteinuria
• immune effects
• glomerular filtration rate
• clinical trials

1. Introduction

This review summarizes the scientific rationale for the use of sparsentan, a novel dual endothelin and angiotensin receptor antagonist (DEARA), in patients with IgA nephropathy (IgAN), the most common primary glomerular disorder in pediatric and adult patients. We present the experience with blockade of angiotensin II (AngII) and endothelin-1 (ET-1) in the treatment of proteinuric kidney disease and update the findings from randomized clinical trials that have been conducted to test the efficacy of sparsentan in IgAN including studies in pediatric patients. We outline the potential role of this DEARA in the management of patients with IgAN as a first-line and adjunctive therapy.

2. Scientific basis for the use of sparsentan in glomerular disorders: non-immune and immune actions

Non-immune: Extensive pre-clinical work in a wide range of models of glomerular disease including IgAN provide strong evidence in support of the key contribution of AngII and ET-1 signaling in the initiation, amplification, and perpetuation of glomerular injury. These peptides interact with membrane receptors on the surface of most cell types intrinsic to the kidney including mesangial cells, endothelial cells, epithelial cells, and podocytes and cause multiple downstream effects [1]. The actions of AngII and ET-1 cause a variety of hemodynamic and structural changes in glomeruli, leading to proteinuria, and ultimately progressive glomerulosclerosis [2]. In addition, AngII and ET-1 trigger inflammation and fibrosis within the tubulointerstitial region leading to tubular atrophy [3]. Moreover, the AngII and ET-1 signaling cascades interact with one another at a molecular level and yield synergistic effects on renal cell function. This observation highlights the potential benefit of administering sparsentan, a novel drug that blocks both AngII type 1 (AT1) and Endothelin Type A (ETA) receptor activation as renoprotective strategy [1].

Immune: These two peptide mediators exert actions on immunoeffector cells. AngII binds to the AT1 receptor and modulates the activity of Th17 and Treg lymphocytes within the kidney [4]. The renal inflammatory and pro-fibrogenic effects of AngII are mediated by interaction with myeloid differentiation protein-2 (MD2), the accessory protein of toll-like receptor 4 (TLR4) of the immune system [5]. Blockade of the AT1 receptor attenuates infiltration by CD8(+) lymphocytes and pro-inflammatory M1 macrophages in a rat model of nephrotoxic serum nephritis. This effect is accompanied by a switch in the cytokine profile from MCP-1, IL-6 and IL-8 to IL-4 and IL-13 with a lessening of kidney injury [6]. AngII also interacts with B-cells, and this contributes to kidney injury. In B-cell-activating factor receptor-deficient (BAFF-R(-/-)) mice that lack mature B cells, there is a lower hypertensive response to AngII compared to wild-type mice. B-cell transfer reversed this vasodepressive response. Pharmacological depletion of B cells with an anti-CD20 antibody attenuated Ang II-induced hypertension by ≈ 35%, a response that is comparable to BAFF-R deficiency [7]. Dahl salt-sensitive (SS) rats have increased sensitivity to dietary sodium-induced hypertension. Intact Dahl SS rats and SS rats deficient in T and B lymphocytes (SS^Rag1-/-) had similar baseline mean arterial blood pressure (MAP) level. While AngII infusion significantly increased MAP in both animal subgroups, MAP increased more rapidly and reached a significantly higher maximal level in wildtype SS rats than SS^Rag1-/- rats after 12 days. The exaggerated hypertensive response was accompanied by increased renal damage, as assessed by albumin excretion rate in SS versus SS^{Rag1-/-g1−/−} rats [8]. Hence, AngII acts via B cells/IgGs to promote hypertension which may exacerbate the progression of glomerular diseases such as IgAN.

Chronic ET-1 infusion in rats promotes increased glomerular and plasma levels of soluble intercellular adhesion molecule-1 and monocyte chemoattractant protein-1. This is accompanied by elevated numbers of macrophages (ED-1) and lymphocytes (CD3) in renal cortices. These changes were attenuated by administration of an ETA receptor selective antagonist [9]. Following ischemia/reperfusion, there is an increase in the number of CD3⁺ T cells in the kidney that is reversed by treatment with an ETA receptor blocker. There are fewer studies linking ET-1 action and inhibition on B cell activity or function [10].

Combined action of AngII and endothelin: The preclinical and clinical evidence supporting a combination of AT1 and ETA receptor inhibition over single blockers of each signaling pathway as a promising approach to treat proteinuric kidney diseases has been reviewed by Komers and Plotkin [1]. Taken together, the studies indicate that dual inhibition of ETA and AT1 receptors has multiple beneficial effects that are superimposed on those achieved by single inhibition of the renin-AngII-aldosterone axis. This has been documented in different models of kidney disease including IgAN, FSGS, and Alport syndrome [11–14]. In contrast to triple-drug therapy with a diuretic, vasodilator, and a centrally acting agent to lower blood pressure, administration of an ETA receptor blocker lowers blood pressure and reduces the number of infiltrating T cells in the interstitium in AngII-mediated hypertension [15,16]. Sparsentan reduced tissue-resident memory T-cells accumulation within the kidney in experimental models of renal disease by inhibiting IL-15 signaling that is activated by AngII and ET-1 [17]. Intra-renal ET-1 gene expression and ET-1 and ETB receptor protein expression are elevated in tissue specimens obtained from patients with IgAN at high risk of disease progression [18–20].

Taken together, findings in experimental models and clinical settings suggest that both AngII and ET-1 exert effects on nonimmune and immune cells and that combined blockade may have beneficial effects on the onset and progression of immune-mediated disorders such as IgAN.

3. Pathogenesis and clinical presentation of IgAN

IgA nephropathy (IgAN), the most common primary glomerular disease worldwide, is now recognized to be a multiple-hit disease [21]. In the initial step, there is aberrant galactosylation of the hinge region of the IgA1 molecule that is synthesized within mucosal tissue. This process may be augmented by local factors such as inflammatory mediators or the gut microbiome and reflect the presence of specific genetic risk loci [22,23]. The abnormal antibody stimulates the production of anti-IgA autoantibodies and the levels of under-galactosylated IgA1 and autoantibodies to the abnormal antibody molecule are correlated with one another [24]. This leads to the formation of soluble circulating immune complexes that are mainly deposited in the mesangial regions of the glomerular tuft. In that location, they stimulate the release of pro-inflammatory and pro-fibrotic mediators by resident glomerular cells and infiltrating immunoeffector cells [25,26]. ET-1 and AngII are important in this response from the start and mediate many deleterious actions. They are activated in response to mesangial deposition of the under-galactosylated IgA-antibody immune complexes, act in tandem to increase mesangial cell proliferation, amplify damage to the glomerular filtration barrier, and lead to tubulointerstitial fibrosis. This ongoing cascade of mesangial and endothelial cell proliferation leads to proteinuria and a decline in glomerular filtration rate. The extent of histological injury is quantitated using the MEST-C scoring system which assesses the extent of mesangial and endothelial hypercellularity, glomerulosclerosis, tubulointerstitial atrophy and fibrosis, and the number of crescents [27].

There are significant variations in the prevalence of IgAN around the globe and in specific racial and ethnic groups [28]. This reflects genetic factors including HLA antigens that contribute to the development and progression of IgAN [29]. Environmental exposures may also contribute to the degree of immunological reaction and severity of IgA nephropathy. Numerous components of the immune system including antibody characteristics and activation of the complement cascade, both the alternative and lectin-binding pathways, are implicated in the kidney injury and progressive decline in kidney function.

IgAN and IgA vasculitis differ clinically in the susceptible age group, nature of their presentation, clinical course, response to treatment, and long-term outcome. However, the current thinking is that, fundamentally, they share a common pathogenesis [30]. Thus, the administration of sparsentan may have clinical benefits in patients with IgA vasculitis. This is being explored in pediatric patients (see below).

Primary IgAN occurs in school-age children, adolescents, and young adults and globally it is the most common primary glomerular disease. It can present with asymptomatic microscopic hematuria, recurrent gross hematuria during or shortly after upper respiratory infections, acute glomerulonephritis, and less commonly with nephrotic syndrome. IgAN has traditionally been considered a relatively benign disease in which only 20–25% of patients experienced progression to kidney failure over an extended period of time, namely 15–20 years. However, based on findings from the RADAR database in the United Kingdom, 40–50% of affected patients with IgAN who have a persistent urine protein-to-creatinine ratio (UPCR) ≥1.0 g:g despite optimal conservative therapy may progress to end-stage kidney disease (ESKD) over a much shorter period of follow-up, namely 5–10 years; moreover, the increased risk of kidney failure may apply for UPCR in the range of 0.5–1 [31]. Although oral corticosteroids and other immunosuppressive drugs such as mycophenolate mofetil are routinely prescribed for patients with IgAN, there are no studies that establish the efficacy of these treatments. These findings underscore the need to develop novel therapies that can reduce proteinuria more effectively than currently available options.

It is worth noting the differences between IgAN and focal segmental glomerulosclerosis (FSGS), the other glomerular disease in which the efficacy of sparsentan has been evaluated. In contrast to IgAN which is an immune-mediated disorder triggered by autoantibodies to abnormally galactosylated IgA1, FSGS is more varied with a range of mechanisms of injury. It is classified as a podocytopathy caused by intrinsic genetic mutations, elaboration of circulating factors that increase glomerular permeability, or unknown factors [32]. Proteinuria is a key manifestation of both glomerular diseases and reduction in urinary protein excretion is an important indicator of treatment response.

4. Sparsentan in IgA nephropathy (IgAN) and the PROTECT phase 3 study

PROTECT is an international, randomized, double-blind, active-controlled study which examined the long-term nephroprotective effects of sparsentan versus irbesartan in adults with biopsy-proven IgA nephropathy.

The PROTECT trial enrolled 404 adults (age ≥18 years) with IgAN at participating sites around the world. The key eligibility criteria were eGFR >30 ml/min/1.73 m² and persistent proteinuria, namely UPCR > 1 despite administration of maximally tolerated doses of renin-AngII–aldosterone axis inhibition with an AngII converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB). They were randomized 1:1 to treatment with irbesartan 300 mg per day (or the maximally tolerated dose) or sparsentan 400 mg per day for 110 weeks [33]. Two hundred and two patients were randomly assigned and received sparsentan and 202 were randomized and received irbesartan. Two hundred and eighty-two [70%] of the 404 included participants were male and 272 [67%] were White.

In a planned pre-specified, interim primary analysis done after 36 weeks of treatment, patients receiving sparsentan achieved a mean reduction in proteinuria from baseline of 49.8%, versus 15.1% for irbesartan-treated patients (p < 0.0001) [34]. Based on these findings, in February 2023 the FDA granted accelerated approval to sparsentan as the first non-immunosuppressive drug to treat adults with primary IgAN at risk of rapid disease progression, generally those with a persistent UPCR ≥1.5 g/g despite treatment with ACEI or ARB for 3–6 months. A Risk Evaluation and Mitigation Strategy (REMS) was required as part of the approval because previous ETA receptor blockers, albeit not sparsentan, have been previously shown to be hepatotoxic. Currently, sparsentan is not approved for the treatment of IgAN in Europe or Japan.

Full analysis of the PROTECT trial outcomes indicated that over 110 weeks, patients in the experimental arm who received sparsentan group had a slower annual rate of eGFR decline compared to those in the irbesartan group. eGFR chronic slope (week 6 to 110, the primary outcome for European Medicines Agency [EMA]), was −2.7 mL/min per 1.73 m² per year versus −3.8 mL/min per 1.73 m² per year in the sparsentan- and irbesartan-treated groups, respectively. The difference was 1.1 mL/min per 1.73 m² per year, 95% CI 0.1 to 2.1, p = 0.037. The total slope (day 1 to week 110, the primary outcome for the US Food and Drug Administration [FDA]) in the two groups was −2.9 mL/min per 1.73 m² per year versus −3.9 mL/min per 1.73 m² per year. The difference was 1.0 mL/min per 1.73 m² per year, 95% CI −0.03 to 1.94, p = 0.·058. The absolute difference in eGFR from baseline to week 110 was 3.7 ml/min/1.73 m² smaller for patients treated with sparsentan versus irbesartan (−5.8 vs −9.5 ml/min/1.73 m², respectively). Follow-up analyses are underway to assess the relationship between the response to sparsentan and the histopathological severity of disease based on MEST-C scoring.

The significant reduction in proteinuria achieved with sparsentan at 36 weeks was sustained and clinically meaningful throughout the entire 110-week treatment phase. Thus, at the end of double-blind treatment, proteinuria reduction, as determined by the change from baseline in UPCR, was significantly lower in the sparsentan group −42.8% (95% CI −49.8 to −35.0) versus −4.4%, (95% CI −15.8 to 8.7) in the irbesartan group. The geometric least-squares mean ratio was 0.60 (95% the 0.50 to 0.72). It is worth noting that the antiproteinuric effect of sparsentan was greater in the PROTECT trial compared to the DUPLEX trial conducted in patients with FSGS [35,36]. A composite clinical endpoint comprised confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality, was reached by 18 (9%) of 202 patients in sparsentan versus 26 (13%) of 202 patients in the irbesartan group. The relative risk was 0.68, 95% CI 0.4 to 1.2). It is important to note that the study was not powered to show differences in this composite endpoint. Blood pressure in the two arms of the study was similar and the modest reduction that occurred early in the treatment period does not account for the sustained beneficial reduction in proteinuria in the sparsentan-treated participants. Similar to the DUET and DUPLEX trials in FSGS, treatment-emergent adverse events were similar in both study arms, with no new sparsentan safety signals in patients with IgAN. The most common adverse events (≥5%) were peripheral edema, hypotension (including orthostatic hypotension), dizziness, hyperkalemia, and anemia and were comparable in the two study arms. Clinically significant edema, fluid overload, and diuretic initiation were not associated with sparsentan, with comparable or greater incidence in the active control irbesartan arm [33,34]. In summary, the findings in the 2-year PROTECT trial demonstrated that sparsentan was safe and well tolerated by adult patients with IgAN, caused a sustained lowering of proteinuria, and reduced the rate of disease progression.

5. Sparsentan in pediatric patients and EPPIK

An ongoing open-label, multicenter Phase 2 basket trial, Study of Sparsentan Treatment in Pediatrics with Proteinuric Glomerular Diseases (EPPIK) (NCT05003986) is active and is evaluating the efficacy of sparsentan treatment for 2 years in children and adolescents with glomerular disease. The test population is patients age 2–18 years and IgAN and IgA vasculitis represent one of the four glomerular diseases being evaluated. The evaluation of long-term use of sparsentan in young patients FSGS will supplement the findings in the DUPLEX trial which had limited pediatric participation, 35 out of 371 (9%) included patients. Of note, Alport syndrome is included in EPPIK based on the finding that sparsentan lowers proteinuria and prolongs survival in a murine model of Alport syndrome, namely deletion of the col43a gene [13,37]. The overall target sample size in the EPPIK study is 57 patients. The primary outcomes are safety and efficacy, i.e. change in UPCR from baseline over the 108-week treatment period. The study is an opportunity to evaluate the use of a liquid formulation of the drug in younger patients. Preliminary data from the first 23 patients who have been enrolled into the study indicate that sparsentan is well tolerated and lowers proteinuria in pediatric patients to the same degree as in adult patients (abstract presentation, ASN meeting 2023).

6. Future applications

Sparsentan can be added to the growing list of newer renoprotective agents that include SGLT2 inhibitors such as dapagliflozin and empagliflozin and non-steroidal mineralocorticoid antagonists such as finerenone. Based on the clinical trial experience of patients with type 2 diabetes and chronic kidney disease, concomitant use of SGLT2 inhibitors with sparsentan may reduce the risk of edema secondary to use of a DEARA like sparsentan [38]. Sparsentan is a useful adjunct to available treatments that are designed to lower proteinuria and may potentially complement the use of immunosuppressive therapies in patients with severe disease based on clinical, laboratory, or histopathology findings. From a patient's perspective, the introduction of sparsentan may reduce pill burden and increase adherence to prescribed medications. This is especially valuable in patients with IgAN in whom recent data underscore the substantial risk of progression to kidney failure even in those with persistent UPCR in the range of 0.5–1.0 [31]. In addition, the quantitative relationship between proteinuria reduction and long-term kidney function outcomes in IgAN highlights the value of sparsentan as another novel agent that is available to nephrologists in their efforts to safely and effectively lower urinary protein excretion [39] Clinical trials are underway to assess the effect of short-term treatment with sparsentan in combination with the other novel renoprotective drugs to define the optimal approach to use in patients with proteinuric kidney disease including IgAN. These studies may be embedded within the open-label extension phase of ongoing randomized clinical trials [40]. The development of reasonably likely surrogate endpoints such as novel measures of changes in proteinuria and eGFR may facilitate accelerated approval of new therapies and foster continued drug development in IgAN and other glomerular diseases [41]. In a precision medicine initiative, a biomarker signature of intra-renal activation of ET-1-specific signaling pathways has been developed and may enable targeting sparsentan to patients most likely to benefit most from the drug [42].

7. Conclusion

Sparsentan is a unique medication that blocks both ETA and AT1 receptors. It is a non-immunosuppressive agent and safely lowers proteinuria and preserves kidney function in patients with IgAN. It may be acting on both resident kidney cells and circulating immune cells to exert its beneficial effect in patients with IgAN. As a non-immunosuppressive medication, sparsentan can be used as a foundation monotherapy to replace RAAS inhibitors as well as in combination with drugs that modulate the immune response. This includes current agents, namely oral and parenteral corticosteroids and antimetabolites, and newer immunosuppressive agents such as budesonide (which has been approved by the fDA for treatment of IgAN), sibeprenlimab, and narsoplimab [43–45]. The 2-year improvement of eGFR of 3.8 ml/min/m² and the clear reduction in chronic eGFR slope in patients with IgAN are strong evidence of renal function benefit. The reduction in eGFR slope will lead to a clinically relevant delay in the need to implement renal replacement therapy. Although the 2-year data from PROTECT demonstrate potential for accrual of benefit over time the extended safety and long-term benefit on protection of kidney function needs to be established. The role of sparsentan in the treatment of pediatric patients with IgAN is under evaluation.

8. Expert opinion

The safety, tolerability, and therapeutic efficacy of sparsentan have been demonstrated in long-term well-designed randomized clinical trials, namely DUET, DUPLEX, and PROTECT extending over 5 years in patients with FSGS. The hitherto evidence in support of a beneficial treatment effect is stronger in patients with IgAN than in FSGS because the drug effectively lowers proteinuria and slows down the rate of disease progression. The findings in the PROTECT trial highlight the importance of previous work that established a quantitative relationship between proteinuria reduction and beneficial clinical outcomes. Similar to other agents that have acute hemodynamic effects and that can cause short-term decreases in eGFR, it will be important to assess the impact of long-term administration of sparsentan to patients with IgAN and to confirm that the reduction in chronic eGFR slope is sustained. This would translate into meaningful delays in the time when renal replacement therapy is needed. The combination of a single medication that blocks angiotensin II and endothelin signaling leverages current understanding of how these two mediators interact to promote worsening kidney injury. From a patient perspective, sparsentan also represents a benefit because it reduces pill burden without compromising therapeutic efficacy. The safety of sparsentan is striking and surpasses the experience with earlier ETA receptor blockers that were associated with heart failure and liver injury. If the safety profile continues to be favorable, the requirement for a REMS system to enable prescription of sparsentan could be lifted which would facilitate more widespread use of the drug.

It will be important to situate sparsentan into an overall scheme of treatment recommendations for patients with IgAN that recognizes the clinical heterogeneity of the disease. It is anticipated that sparsentan will supplant the use of ACEI or ARB as the first-line therapy in nearly all patients to reduce proteinuria over 3–6 months prior to the implementation of immunosuppressive agents because it is more effective than use of RAAS inhibitor agents alone. It may be combined with other renoprotective drugs like SGLT2 inhibitors or non-steroidal mineralocorticoid antagonists during this nonspecific renoprotective phase of treatment. Trials are ongoing to assess the efficacy of combination drug regimens. Sparsentan may be combined with immunosuppressive drugs in patients with severe manifestation at the disease onset or rapid decline in kidney function while receiving sparsentan and other renoprotective drugs. The choice of prednisone or other immunosuppressive agents should be guided by the circumstances of each individual patient. The assessment of disease severity and acuity should incorporate renal biopsy findings including the MEST-C score. Those with active proliferative lesions including severe endocapillary hypercellularity and crescents are likely to benefit from continued immunosuppressive therapy while those with chronic lesions such as glomerulosclerosis and tubular atrophy/interstitial fibrosis may be best managed solely with sparsentan and other nonspecific agents [46].

The findings that sparsentan is effective in patients with Alport syndrome are encouraging in light of recent data documenting the higher than expected prevalence of collagen-gene mutations in patients with other glomerular disease diagnoses. While work is needed to assess the safety and efficacy of sparsentan as a renoprotective agent in the wider range of glomerular diseases including lupus nephritis and ANCA-associated vasculitis, it is likely that the drug will have a prominent place in the care of these patients as well. Educational programs to increase familiarity with the mechanism of action of sparsentan, clinical benefits and adverse effects, and practice guidelines will promote safe and effective use of this new drug by nephrologists caring for patients with IgAN in all clinical settings. Non-invasive biomarker profiles are being developed that identify patients with glomerular diseases like IgAN in whom the endothelin signaling pathway is activated and mediating glomerular and tubulointerstitial injury. Future research assessing the profile of predictive biomarkers may enable precision medicine guided use of sparsentan and target the drug to individual patients with IgAN who are most likely to benefit from its use.

Article highlights

• Endothelin-1 and angiotensin II signaling are activated in patients with glomerular diseases such as IgA nephropathy.

• Sparsentan reduces proteinuria and slows the rate of decline in kidney function in patients with IgA nephropathy.

• Sparsentan is safe and well tolerated in patients with IgA nephropathy.

• Sparsentan is a valuable addition to current therapy for IgA nephropathy as a single agent for those with low-grade proteinuria or in combination with imunosuppressive agents in those with moderate-to-severe proteinuria or declining kidney function.

• Ongoing assessment will be needed to confirm the long-term efficacy of sparsentan in the treatment of IgA nephropathy and to delineate its optimal use in the context of the full spectrum of available renoprotective therapies.

Declaration of interests

H Trachtman is a consultant to Travere Therapeutics Inc and Jula Inrig and Radko Komers are employees of Travere Therapeutics Inc. and own shares of the company. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.