Status of current trials and potential future trials with sparsentan

KEYWORDS:

• Sparsentan
• IgA nephropathy
• focal segmental glomerulosclerosis
• proteinuria
• glomerular filtration rate
• clinical trials

1. Scientific rationale for the use of sparsentan in proteinuric kidney disease

This editorial summarizes the scientific rationale for the use of sparsentan in proteinuric kidney disease. It reviews the ongoing randomized clinical trials of the drug in IgA nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS) as well as studies in pediatric patients and outlines the potential role of sparsentan in the future management of patients with proteinuric kidney disease.

There is abundant evidence supporting the role of angiotensin II (AngII) and endothelin-1 (ET-1) signaling in the pathogenesis and perpetuation of glomerular injury. These vasoactive molecules act on mesangial and endothelial cells and podocytes, causing a variety of pathological changes in glomeruli, leading to proteinuria, and ultimately progressive glomerulosclerosis. Moreover, these signaling cascades interact with one another underscoring the potential application of sparsentan, a novel non-immunosuppressive dual endothelin and angiotensin receptor antagonist (DEARA) that blocks AT1 and Endothelin Type A (ETA) receptor activation

The preclinical and clinical evidence supporting the use of dual AT1/ETA receptor inhibition over monoblockers of AngII or ET-1 actions in the treatment of kidney diseases has been reviewed by Komers and Plotkin [1]. Recent findings reinforce the value of specifically inhibiting ET-1 in patients with glomerular disease. Endothelin gene expression is elevated in patients with glomerular disease such as IgA nephropathy and an increased risk of disease progression [2]. Preclinical studies with sparsentan demonstrated a spectrum of antiproliferative, anti-inflammatory, antifibrotic, and podocyte-protective actions of the drug in different models of kidney disease including FSGS, IgAN, and Alport syndrome [3–6]. A novel protective mechanism of sparsentan in FSGS was recently suggested by Li et al. [7]. The abundance of tissue-resident lymphocytes and the proportion of CD8⁺ T_RM cells are increased in kidneys from patients with FSGS. Sparsentan reduced T_RM cell responses by inhibiting Ang II and/or ET-1-mediated IL-15 signaling, thereby further regulating renal CD8⁺ T_RM cell accumulation in the kidney [5]. ETA receptor expression is increased in kidney biopsy specimens obtained from patients with FSGS, and the intensity is directly related to nephron loss and oxidative damage. The degree of oxidative stress is, in turn, associated with proteinuria [8,9].

2. Sparsentan in IgA nephropathy (IgAN) and PROTECT

Primary glomerular disorders are an important cause of kidney failure. Current therapies are not consistently effective in achieving remission of proteinuria. Moreover, available treatments are associated with significant side effects that limit tolerance and efficacy. There is an urgent need to develop novel therapies that can safely reduce proteinuria and preserve renal function.

Primary IgAN is the most common glomerular disease detected on kidney biopsy in patients with urinary abnormalities. It was originally considered a relatively benign disease in which a minority of patients experienced worsening kidney function and even then over an extended period of time. However, adults with IgAN who have a urine protein-to-creatinine ratio (UPCR) ≥1.5 g/g despite intensive treatment with agents that block the renin angiotensin aldosterone axis are now recognized to be at increased risk of rapid disease progression. Specifically, based on findings from the RADAR database in the United Kingdom, nearly 40–50% of affected patients will progress to end-stage kidney disease (ESKD) over 5–10 years of follow-up [10]. These findings underscore the need to develop novel therapies that can reduce proteinuria more effectively than currently available drugs

The PROTECT trial enrolled 404 patients age ≥18 years with IgAN and persistent proteinuria defined as UPCR ≥1.5 g/g despite administration of maximal tolerated doses of angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB). They were randomized 1:1 to treatment with irbesartan 300 mg per day or sparsentan 400 mg per day for 104 weeks [11]. A pre-specified, primary analysis showed that after 36 weeks of treatment, patients receiving sparsentan achieved a mean reduction in proteinuria from baseline of 49.8%, compared to a mean reduction in proteinuria from baseline of 15.1% for irbesartan-treated patients (p < 0.0001) [12]. A post-hoc sensitivity analysis performed at the request of the FDA evaluated the first 281 randomized patients, a subset of the full trial population. The mean reduction in proteinuria from baseline in the post-hoc sensitivity analysis was 45% for sparsentan versus 15% for irbesartan.

Both the pre-specified and post-hoc sensitivity analyses demonstrated that sparsentan achieves a rapid and sustained reduction in proteinuria, with statistically significant and clinically meaningful improvement compared to the active comparator irbesartan. Sparsentan was well tolerated with a clearly defined safety profile that has been consistent across all clinical trials conducted to date. Thus, in PROTECT, the most common adverse reactions (≥5%) were peripheral edema, hypotension (including orthostatic hypotension), dizziness, hyperkalemia, and anemia [12]. Based on these findings, in February 2023 the FDA granted accelerated approval to sparsentan as the first non-immunosuppressive drug to reduce proteinuria in adults with primary IgAN at risk of rapid disease progression, namely those with a UPCR ≥1.5 g/g. Because of the potential risk of liver injury and birth defects, sparsentan is available for use only through a Risk Evaluation and Mitigation Strategy (REMS) approved by the FDA. Currently, sparsentan is not approved for the treatment of IgAN in Europe or Japan.

3. Sparsentan in focal segmental glomerulosclerosis (FSGS) and DUPLEX

Patients with primary FSGS and persistent proteinuria are at increased risk of progression to ESKD. In the DUPLEX Study, a total of 371 patients, age 8–75 years, with FSGS and a UPCR ≥1.5 g/g were randomized 1:1 to receive either 800 mg of sparsentan or 300 mg of irbesartan, the active control irbesartan for 2 years. The DUPLEX study represents the largest randomized clinical trial that has ever been conducted for FSGS. The dose of sparsentan tested in DUPLEX was higher than in PROTECT because of the greater degree of proteinuria and the greater severity of disease in patients with FSGS. The diagnosis of FSGS was based on the characteristic findings in a kidney biopsy or documentation of a pathogenic genetic mutation and the absence of a clinically apparent secondary cause of the disease [13]. The study protocol provided for an unblinded analysis to evaluate a novel interim efficacy endpoint – the proportion of patients achieving the FSGS partial remission endpoint (FPRE), which is a clinically meaningful endpoint defined as UPCR ≤1.5 g/g and a >40% reduction in UPCR from Baseline at Week 36 [14].

Following the first 190 patients reaching 36 weeks of treatment, 42% of patients receiving sparsentan achieved FPRE, compared to 26% of irbesartan-treated patients (p = 0.0094). Analysis of the primary outcomes after the 108-week treatment phase in the DUPLEX study indicated that sparsentan was associated with a 0.9 ml/min/1.73 m² per year reduction in the chronic slope of eGFR, defined as the rate of decline in eGFR after the hemodynamically mediated reduction during the initial 6 weeks of treatment, compared to the active control irbesartan arm. Although this difference was not statistically significant, it does suggest a potential clinical benefit in delaying the onset of ESKD. In addition, treatment with sparsentan achieved a mean reduction in proteinuria from a baseline of 50%, compared to 32% for irbesartan. The quantitative reduction in proteinuria was paralleled by an increased percentage of patients who were treated with sparsentan who achieved the FPRE outcome or a complete remission (UPCR <0.3) versus irbesartan therapy.

The overall results from the 2-year analysis demonstrated that sparsentan was well tolerated and has a comparable safety profile to irbesartan with no worsening of edema or occurrence of major cardiovascular or hepatic adverse events. Similar to the PROTECT trial, no unanticipated adverse effects have been noted. Future work may include delineation of the impact of biomarker profiles that characterize activation of specific signaling pathways as prognostic indicators to guide the use of sparsentan in FSGS and other proteinuric kidney diseases.

4. Sparsentan in pediatric patients and EPPIK

An ongoing Phase 2 basket trial, study of Sparsentan Treatment in Pediatrics With Proteinuric Glomerular Diseases (EPPIK) (NCT05003986) is underway to assess the efficacy of sparsentan as an antiproteinuric agent in children and adolescents with glomerular disease. The study is open label in design, and patients age 2–18 years with one of the following four glomerular disorders are eligible for enrollment [1]: FSGS [2]; minimal change disease [3]; IgAN and IgA vasculitis; and [4] Alport syndrome. The inclusion of the fourth category is based on preclinical data demonstrating the efficacy of sparsentan to reduce proteinuria and prolong survival in a murine model of Alport syndrome, namely deletion of the col43a gene [3,15]. Treatment is being provided for 2 years, and the primary outcomes are focusing on safety, i.e. incidence of treatment-emergent adverse events (TEAEs), and efficacy, i.e., change from baseline in UPCR over the 108-week treatment period.

5. Future applications

A number of novel non-immunosuppressive therapies have recently been identified that have a renoprotective effect that is additive to standard treatment with inhibitors of the renin-angiotensin-aldosterone axis. These agents, including SGLT2 inhibitors such as dapagliflozin and empagliflozin and non-steroidal mineralocorticoid antagonists such as finerenone, act on different pathways. The greatest effect on proteinuria and eGFR may be achieved with rational combination therapy of these drugs as well as adjunctive treatment with immunosuppressive agents. Therefore, clinical trials are being designed to assess the effect of short-term treatment with sparsentan in combination with these other drugs to better define the optimal approach to use them in patients with proteinuric kidney disease. Efforts are being made to embed these studies within the open-label extension phase of ongoing clinical trials [16]. The effect of sparsentan on proteinuria and the trajectory of kidney function warrants investigation in a broader spectrum of glomerular diseases. This may be facilitated by the identification of a biomarker signature that indicates intra-renal activation of specific signaling pathways and patients who are likely to benefit from sparsentan therapy.

6. Conclusion

Sparsentan, a novel dual endothelin and angiotensin receptor antagonist (DEARA), has been shown to lower proteinuria and preserve kidney function in preclinical models of glomerular disease. Emerging clinical data support the use of sparsentan for the treatment of primary glomerular disease, specifically in IgAN and FSGS, based on its strong antiproteinuric effect. As a non-immunosuppressive medication, it may be a useful adjunctive therapy for patients being treated with drugs that modulate the immune response. The long-term benefit on protection of kidney function still needs to be established. Studies are ongoing to extend the findings to pediatric patients. Sparsentan represents a potentially useful non-immunologically based treatment option that can be incorporated into routine care of patients with proteinuric kidney disease as a nephroprotective agent.

7. Expert opinion

The safety and tolerability of sparsentan has been demonstrated in long-term studies extending over 5 years, namely in patients who have received the drug in the DUET open-label extension phase (manuscript in preparation). However, long-term follow-up is needed to confirm the safety and beneficial effect of sparsentan on clinical outcomes in patients with IgAN and FSGS. These findings provide the basis for further study in a broad range of patients across the lifespan with proteinuric kidney disease who might benefit from treatment with this non-immunologically based agent. In view of its dual actions, we anticipate that sparsentan may supplant the use of ACEI or ARB as a first-line therapy to reduce proteinuria prior to the implementation of second-line agents including immunosuppressive agents in patients with IgAN. Its optimal use in the context of other available antiproteinuric agents will emerge in clinical trials assessing safety and efficacy of sparsentan as a solitary agent or in combination with other drugs. In those with FSGS, sparsentan may be the initial drug that is prescribed in those with subnephrotic-range proteinuria or be used in conjunction with other treatments in patients with higher grade proteinuria or edema. The application to other conditions such as lupus nephritis, ANCA-associated vasculitis, and Alport syndrome requires further investigation. Educational programs are warranted to increase familiarity with the mechanism of action of sparsentan, potential clinical benefits and adverse effects, and optimal monitoring procedures to promote use of this new drug by nephrologists caring for patients with proteinuric kidney disease in all clinical settings.

Declaration of interest

H Trachtman is a consultant to Travere Therapeutics Inc. R Komers and J Inrig are employed by Travere Therapeutics, Inc. 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 apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have participated in a scientific board meeting regarding the role of sparsentan in the two trials mentioned. However, they did not receive personal financial support for it. They have also disclosed that their institution was invited to participate in the two trials with sparsentan but could not include patients in the trial. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.