Expert Review of Clinical Immunology

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Sparsentan: the first and only non-

immunosuppressive therapy for the reduction of
proteinuria in IgA nephropathy

Howard Trachtman, Radko Komers & Jula Inrig

To cite this article: Howard Trachtman, Radko Komers & Jula Inrig (26 Feb 2024): Sparsentan:
the first and only non-immunosuppressive therapy for the reduction of proteinuria in IgA
nephropathy, Expert Review of Clinical Immunology, DOI: 10.1080/1744666X.2024.2319132

To link to this article: https://doi.org/10.1080/1744666X.2024.2319132

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EXPERT REVIEW OF CLINICAL IMMUNOLOGY
https://doi.org/10.1080/1744666X.2024.2319132

DRUG PROFILE

Sparsentan: the first and only non-immunosuppressive therapy for the reduction of
proteinuria in IgA nephropathy
Howard Trachtmana, Radko Komersb and Jula Inrigb
a
Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA; bTravere Therapeutics, Inc, San Diego, CA, USA

ABSTRACT ARTICLE HISTORY

Introduction: IgA nephropathy is one of the most common forms of glomerular disease. Patients with Received 30 December 2023
persistent proteinuria are at increased risk of progression to kidney failure. There is a significant need Accepted 12 February 2024
for safe and effective therapies to lower proteinuria in these patients. Sparsentan is a non- KEYWORDS
immunosuppressive agent that acts as a dual angiotensin and endothelin receptor antagonist. It lowers Sparsentan; IgA
proteinuria in experimental models of glomerular disease and in affected patients. nephropathy; proteinuria;
Areas covered: This review covers the immunological and non-immunological actions of sparsentan in immune effects; glomerular
glomerular disease. It reviews the clinical trials that evaluated the impact of the drug in pediatric and filtration rate; clinical trials
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 immunosup­
pressive 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.

1. Introduction receptors on the surface of most cell types intrinsic to the

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
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 hemody­
namic and structural changes in glomeruli, leading to protei­
nuria, 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(+) lympho­
cytes and pro-inflammatory M1 macrophages in a rat model

CONTACT Howard Trachtman howardtrachtman21@gmail.com Division of Nephrology, Department of Pediatrics, Taubman Health Sciences Center,
University of Michigan, 1135 Catherine St., Ann Arbor, MI 48109, USA
© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.
2 H. TRACHTMAN ET AL.
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 nephro­
pathy 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.
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 (SSRag1-/-) 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 SSRag1-/- rats after 12 days. The
exaggerated hypertensive response was accompanied by
increased renal damage, as assessed by albumin excretion
rate in SS versus SSRag1-/-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 glomeru­
lar and plasma levels of soluble intercellular adhesion mole­
cule-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 path­
way as a promising approach to treat proteinuric kidney dis­
eases 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 hyper­
tension [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 clin­
ical 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 glomeru­
lar 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 micro­
biome 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 forma­
tion 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 mesan­
gial deposition of the under-galactosylated IgA-antibody
immune complexes, act in tandem to increase mesangial cell
proliferation, amplify damage to the glomerular filtration bar­
rier, and lead to tubulointerstitial fibrosis. This ongoing cas­
cade 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, tubulointersti­
tial 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 con­
tribute 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 anti­
body characteristics and activation of the complement cas­
cade, 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 micro­
scopic hematuria, recurrent gross hematuria during or shortly
after upper respiratory infections, acute glomerulonephritis,
and less commonly with nephrotic syndrome. IgAN has tradi­
tionally 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 evalu­
ated. In contrast to IgAN which is an immune-mediated dis­
order 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 circulat­
ing factors that increase glomerular permeability, or unknown
factors [32]. Proteinuria is a key manifestation of both glomer­
ular 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 nephropro­
tective 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
EXPERT REVIEW OF CLINICAL IMMUNOLOGY 3
proteinuria, namely UPCR > 1 despite administration of maxi­
mally 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 sparsen­
tan 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, sparsen­
tan 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 differ­
ence 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 trea­
ted 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 spar­
sentan 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 deter­
mined 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 spar­
sentan 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
4 H. TRACHTMAN ET AL.
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 per­
ipheral 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 protei­
nuria, 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 ado­
lescents 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 participa­
tion, 35 out of 371 (9%) included patients. Of note, Alport syn­
drome 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 presenta­
tion, ASN meeting 2023).
6. Future applications
Sparsentan can be added to the growing list of newer renopro­
tective agents that include SGLT2 inhibitors such as dapagliflozin
and empagliflozin and non-steroidal mineralocorticoid antago­
nists such as finerenone. Based on the clinical trial experience of
patients with type 2 diabetes and chronic kidney disease, conco­
mitant 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 medica­
tions. 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 spar­
sentan 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 signa­
ture 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 corticos­
teroids 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 imple­
ment 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 clin­
ical 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 med­
ication that blocks angiotensin II and endothelin signaling
leverages current understanding of how these two mediators
interact to promote worsening kidney injury. From a patient per­
spective, 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 sparsen­
tan 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 recog­
nizes 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 treat­
ment. 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 circum­
stances 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 spar­
sentan and other nonspecific agents [46].
The findings that sparsentan is effective in patients with
Alport syndrome are encouraging in light of recent data docu­
menting 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 spar­
sentan as a renoprotective agent in the wider range of glomer­
ular 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
EXPERT REVIEW OF CLINICAL IMMUNOLOGY 5
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.
Funding
This paper was not funded.
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 manu­
script. 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.
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