Current status of Filspari (Sparsentan) in the United States: FDA approved indications for Filspari (Sparsentan): To slow kidney function decline in adults with primary immunoglobulin A nephropathy (IgAN) who are at risk for disease progression

Implications of all the available evidence

Although the value of lowering proteinuria in patients with IgA nephropathy has been established for some time, it has become increasingly clear that patients with proteinuria below the commonly used threshold of 1·0 g per day (KDIGO guidelines) are still at risk of progression to kidney failure. A reasonable interpretation of the collective data is that the management goal for IgA nephropathy is to reduce proteinuria in individual patients as much as possible and well below 1·0 g per day if this can be done safely. The recent trials in IgA nephropathy have shown that systemic glucocorticoids, gut-targeted glucocorticoids, and sparsentan lower proteinuria more effectively than RAS blockade alone and that this additional reduction in proteinuria provides a significant benefit to preservation of the glomerular filtration rate. Importantly, each of these therapeutics acts through different pathways, suggesting that combination therapy is likely to be additive in terms of proteinuria reduction and preservation of kidney function. Because sparsentan is not an immunosuppressive agent, we suggest its placement in the IgA nephropathy treatment paradigm as a long-term foundational therapy upon which immunosuppressive agents can be used intermittently as required to achieve maximum proteinuria suppression to prolong kidney survival in patients with IgA nephropathy.

To address this unmet need, the PROTECT trial focused on the potential therapeutic application of dual endothelin-1 and angiotensin II antagonism to treat IgA nephropathy using sparsentan, a non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist with high selectivity for the endothelin receptor type A (ETAR) and angiotensin II receptor type 1 (AT1R). Endothelin-1, via activation of ETAR on multiple kidney cell types, plays a key part in driving many processes associated with nephron loss in kidney disease, including vasoconstriction, cell proliferation, inflammation, apoptosis, and fibrosis.

Immunoglobulin A (IgA) nephropathy is the most common primary glomerulonephritis and an important cause of kidney failure. Proteinuria has been consistently shown to be a risk factor for progressive kidney function loss in patients with IgA nephropathy, and remission of proteinuria is associated with improved kidney outcomes. Despite the risk of progressive kidney disease and kidney failure, few therapeutic options are available. The Kidney Disease Improving Global Outcomes (KDIGO) guideline recommends the use of renin-angiotensin system (RAS) inhibitors in patients with proteinuria more than 0·5 g/day. Following 3 months of RAS inhibitor treatment, patients with proteinuria of 1 g/day or higher have a greater risk of disease progression, and additional treatment is recommended.

The use of RAS inhibitors as standard of care in IgA nephropathy is based on their well established pleiotropic nephroprotective actions in a variety of kidney diseases and indicates a contribution of its main effector, angiotensin II, in the pathophysiology of IgA nephropathy. More recently, advances in our understanding of the pathogenesis of IgA nephropathy show that endothelin-1 (ET-1) contributes to the pathophysiology of IgA nephropathy via activation of ETAreceptors, leading to a variety of effects including vasoconstriction, podocyte dysfunction, tubular injury, inflammation, and fibrosis. Similar to RAS inhibitors, ETAreceptor antagonists have shown a wide range of beneficial effects in various models of glomerular diseases. Therefore, a strong rationale exists for a therapeutic approach with simultaneous antagonism of these two pathways that act in tandem, in order to protect kidney function. Indeed, the actions of RAS inhibitors and ETAreceptor antagonists in combination have demonstrated additional benefits in experimental models of kidney disease and in patients with both diabetic and non-diabetic nephropathies, including IgA nephropathy.

In a previous report we demonstrated that merging together key structural elements present in an AT(1) receptor antagonist (1, irbesartan) with key structural elements in a biphenylsulfonamide ET(A) receptor antagonist (2) followed by additional optimization provided compound 3 as a dual-action receptor antagonist (DARA), which potently blocked both AT(1) and ET(A) receptors. Described herein are our efforts directed toward improving both the pharmacokinetic profile as well as the AT(1) and ET(A) receptor potency of 3. Our efforts centered on modifying the 2'-side chain of 3 and examining the isoxazolylsulfonamide moiety in 3. This effort resulted in the discovery of 7 as a highly potent second-generation DARA. Compound 7 also showed substantially improved pharmacokinetic properties compared to 3. In rats, DARA 7 reduced blood pressure elevations caused by intravenous infusion of Ang II or big ET-1 to a greater extent and with longer duration than DARA 3 or AT(1) or ET(A) receptor antagonists alone. Compound 7 clearly demonstrated superiority over irbesartan (an AT(1) receptor antagonist) in the normal SHR model of hypertension in a dose-dependent manner, demonstrating the synergy of AT(1) and ET(A) receptor blockade in a single molecule.

The ET(A) receptor antagonist (2) (N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-[1,1'-biphenyl]-2-sulfonamide, BMS-193884) shares the same biphenyl core as a large number of AT(1) receptor antagonists, including irbesartan (3). Thus, it was hypothesized that merging the structural elements of 2 with those of the biphenyl AT(1) antagonists (e.g., irbesartan) would yield a compound with dual activity for both receptors. This strategy led to the design, synthesis, and discovery of (15) (4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-[1,1'-biphenyl]-2-sulfonamide, BMS-248360) as a potent and orally active dual antagonist of both AT(1) and ET(A) receptors. Compound 15 represents a new approach to treating hypertension.

A series of 4'-[(benzimidazole-1-yl)methyl]biphenyl-2-sulfonamide derivatives (Ia-Il) were synthesized and biologically evaluated. It was found that Ig, the most active compound, antagonized both Ang II AT(1) and endothelin ET(A) receptors (AT(1) IC(50)=8.5, ET(A) IC(50)=8.9 nM), and was more potent than losartan in RHRs with no significant effect on heart rate. The preliminary structure-activity relationships were also discussed in the present paper.

Endothelin and angiotensin II are potent vasoconstrictor substances that also can exert proliferative and proinflammatory effects. Dysregulation of these systems can induce or mediate endothelial dysfunction and organ damage in systemic hypertension. Dual-acting angiotensin II and endothelin receptor blockers have been shown to reduce systemic blood pressure in animal models and in hypertensive patients. Preliminary data in smaller human studies have shown that these agents are safe and well tolerated. Larger randomized trials evaluating the efficacy and safety of these agents are underway and show potential as a new class of antihypertensives.

Angiotensin II and endothelin-1 activate their respective AT(1) and ET(A) receptors on vascular smooth muscle cells, producing vasoconstriction, and both peptides are implicated in the pathogenesis of essential hypertension. Angiotensin II potentiates the production of endothelin, and conversely endothelin augments the synthesis of angiotensin II. Both AT(1) and ET(A) receptor antagonists lower blood pressure in hypertensive patients; thus, a combination AT(1)/ET(A) receptor antagonist may have greater efficacy and broader utility compared with each drug alone. By rational drug design a biphenyl ET(A) receptor blocker was modified to acquire AT(1) receptor antagonism. These compounds (C and D) decreased Sar-Ile-Angiotensin II binding to AT(1) receptors and endothelin-1 binding to ET(A) receptors, and compound C inhibited angiotensin II- and endothelin-1-mediated Ca(2+) transients. In rats compounds C and D reduced blood pressure elevations caused by intravenous infusion of angiotensin II or big endothelin-1. Compound C decreased blood pressure in Na(+)-depleted spontaneously hypertensive rats and in rats with mineralocorticoid hypertension. Compound D was more efficacious than AT(1) receptor antagonists at reducing blood pressure in spontaneously hypertensive rats, and its superiority was likely due to its partial blockade of ET(A) receptors. Therefore compounds C and D are novel agents for treating a broad spectrum of patients with essential hypertension and other cardiovascular diseases.

A series of 4'-[(imidazol-1-yl)methyl]biphenylsulfonamides has potent antagonist activity against both angiotensin II AT(1) and endothelin ET(A) receptors. Such dual-acting antagonists could have utility in the treatment of hypertension, heart failure, and other cardiovascular diseases in a broad patient population. Certain compounds in the present series are orally active in a rat model of angiotensin II-mediated hypertension.

A new series of phosphinic inhibitors able to interact with both angiotensin-converting enzyme (ACE) C-domain and endothelin-converting enzyme-1 (ECE-1), while sparing neprilysin (NEP), has been developed. The most potent and selective inhibitor in this series (compound 8(F2)) displays K(i) values of 0.65 nM, 150 nM, 14 nM and 6.7 microM toward somatic ACE C-domain, ACE N-domain, ECE-1, and NEP, respectively. Remarkably, in this series, the inhibitor's ability to discriminate between ECE-1 and NEP was observed to depend on the stereochemistry of the residue present in the inhibitor's P(1)' position. After iv administration, compound 8(F2) (10 mg/kg) lowered mean arterial blood pressure by 24 +/- 2 mmHg in spontaneously hypertensive rats, as compared with controls. Mixed ACE/ECE-1 inhibitor may lead to a new generation of vasopeptide inhibitors that should reduce the levels of angiotensin-II and endothelin-1, without interfering with bradykinin cleavage.