Nej Mo A 2409415

The n e w e ng l a n d j o u r na l of m e dic i n e
Original Article
Atrasentan in Patients with IgA Nephropathy

Hiddo J.L. Heerspink, Ph.D., Meg Jardine, M.B., B.S., Ph.D.,
Donald E. Kohan, M.D., Ph.D., Richard A. Lafayette, M.D., Adeera Levin, M.D.,
Adrian Liew, M.D., Hong Zhang, Ph.D., Amit Lodha, M.B., B.S.,
Todd Gray, M.S.P.H., Yi Wang, Ph.D., Ronny Renfurm, M.D.,
and Jonathan Barratt, M.D., for the ALIGN Study Investigators*
A BS T R AC T
BACKGROUND
Patients with IgA nephropathy and severe proteinuria have a high lifetime risk of From the Department of Clinical Phar-
kidney failure. The efficacy and safety of the selective endothelin type A receptor macy and Pharmacology, University of
Groningen, University Medical Center
antagonist atrasentan in reducing proteinuria in patients with IgA nephropathy are Groningen, Groningen, the Netherlands
incompletely understood. (H.J.L.H.); the National Health and Med-
ical Research Council Clinical Trials Cen-
METHODS tre, University of Sydney, Sydney (M.J.);
the Division of Nephrology, University of
We are conducting a phase 3, multinational, double-blind, randomized, controlled Utah Health, Salt Lake City (D.E.K.);
trial involving adults with biopsy-proven IgA nephropathy, a total urinary protein Stanford University, Stanford, CA (R.A.L.);
excretion of at least 1 g per day, and an estimated glomerular filtration rate of at the University of British Columbia, Van-
couver, Canada (A. Levin); Mount Eliza-
least 30 ml per minute per 1.73 m2 of body-surface area. Patients were randomly beth Novena Hospital, Singapore (A. Liew);
assigned to receive atrasentan (0.75 mg per day) or matched placebo for 132 weeks. Peking University First Hospital, Beijing
The primary outcome, assessed at a prespecified interim analysis of data from the (H.Z.); Chinook Therapeutics, Seattle
(T.G.); Novartis, East Hanover, NJ (A.
first 270 patients in the main stratum, was the change in the 24-hour urinary Lodha, Y.W.); Novartis, Basel, Switzer-
protein-to-creatinine ratio from baseline to week 36; the change was estimated land (R.R.); and the University of Leices-
with the use of a repeated-measures model. (An exploratory stratum of patients ter, Leicester, United Kingdom (J.B.). Dr.
Heerspink can be contacted at h.j.lambers
who were receiving a sodium–glucose cotransporter 2 inhibitor were included in .heerspink@umcg.nl or at University Med-
a separate analysis.) Safety analyses were based on adverse events across the entire ical Center Groningen, Hanzeplein 1, PO
main stratum. Box 30 001, 9700 RB Groningen, the
Netherlands.
RESULTS *A complete list of the ALIGN Study
A total of 340 patients were recruited into the main stratum. Among the first 270 Investigators is available in the Supple-
patients in the main stratum (135 per trial group) who completed the week 36 mentary Appendix, available at NEJM.org.
visit, the geometric mean percentage change in the urinary protein-to-creatinine This article was published on October 25,
ratio relative to baseline was significantly greater with atrasentan (−38.1%) than 2024, at NEJM.org.
with placebo (−3.1%), with a geometric mean between-group difference of −36.1 DOI: 10.1056/NEJMoa2409415
percentage points (95% confidence interval, −44.6 to −26.4; P<0.001). The percent- Copyright © 2024 Massachusetts Medical Society.
age of patients with adverse events did not differ substantially between the two
groups. Fluid retention was reported by 19 of 169 patients (11.2%) in the atrasen-
tan group and in 14 of 170 (8.2%) in the placebo group but did not lead to discon-
tinuation of the trial regimen. No apparent cases of cardiac failure or severe edema
occurred.
CONCLUSIONS
In this prespecified interim analysis, atrasentan resulted in a significant and
clinically meaningful reduction in proteinuria as compared with placebo in pa-
tients with IgA nephropathy. (Funded by Novartis; ALIGN ClinicalTrials.gov num-
ber, NCT04573478.)
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I
gA nephropathy is the most common sight of the trial and reporting of the results. The
primary glomerular disease in the world and trial protocol (available at NEJM.org) was ap-
is associated with a substantial lifetime risk proved by a central or local ethics committee at
of kidney failure.1,2 Current guideline-recom- each trial site, and the statistical analysis plan is
mended treatment of IgA nephropathy is focused available with the protocol. All the patients pro-
on reducing proteinuria and slowing progressive vided written informed consent. The interim anal-
loss of kidney function with nonimmunosup- ysis was conducted by the sponsor. The first draft
pressive therapies, including lifestyle modifica- of the manuscript was written by the first and last
tion and renin–angiotensin system (RAS) inhibi- authors and revised by the coauthors. Technical
tion.3 However, despite these treatments, the risk editorial assistance was provided by the sponsor.
of kidney failure remains high, which highlights The authors had access to the full data set and
the need for new therapies that target different vouch for the completeness and accuracy of the
aspects of the disease pathophysiology. data and for the fidelity of the trial to the proto-
Endothelin-1 is a vasoactive peptide implicat- col. The decision to submit the manuscript for
ed in the pathophysiology of IgA nephropathy. publication was made jointly by all the authors.
Binding of endothelin-1 to the endothelin type A
receptor in the kidney causes endothelial and Patients
podocyte damage, mesangial expansion, and tu- Adults (≥18 years of age) with biopsy-proven IgA
bular inflammation in experimental models of nephropathy, a total urinary protein excretion of
IgA nephropathy.4,5 Atrasentan, a selective inhibi- at least 1 g per day, and an eGFR of at least 30 ml
tor of the endothelin type A receptor, exerts an- per minute per 1.73 m2 of body-surface area were
tiproliferative, antifibrotic, and antiinflammatory eligible for participation. Treatment with a max-
effects in experimental models of IgA nephropa- imum tolerated dose of an ACE inhibitor or ARB
thy.6,7 In the IgA nephropathy stratum of the at a stable dose for at least 12 weeks before screen-
open-label AFFINITY basket trial, the addition of ing was required. Patients who were unable to
atrasentan to maximum tolerated doses of angio- take RAS inhibitors were eligible; however, the
tensin-converting–enzyme (ACE) inhibitors or total percentage of such patients could not exceed
angiotensin-receptor blockers (ARBs) reduced the 5% of the total population. Key exclusion criteria
24-hour urinary protein-to-creatinine ratio by were secondary IgA nephropathy, a documented
48% after 12 weeks of treatment.8 Moreover, diagnosis of heart failure or previous hospital-
among patients with type 2 diabetes and chron- ization for heart failure, or a B-type natriuretic
ic kidney disease, atrasentan reduced the risk of peptide (BNP) level of more than 200 pg per
a composite of doubling of the serum creatinine milliliter. Patients who were receiving a stable
level or kidney failure by 35%.9 dose of a sodium–glucose cotransporter 2 (SGLT2)
Here we present the results of a prespecified inhibitor could be enrolled in an exploratory
analysis of the ALIGN trial, which is assessing SGLT2 inhibitor stratum in regions where SGLT2
the efficacy and safety of atrasentan as com- inhibitors were available and approved. This ex-
pared with placebo in reducing proteinuria and ploratory SGLT2 inhibitor stratum was indepen-
the decline in the estimated glomerular filtration dent of the main stratum. Full inclusion and ex-
rate (eGFR) in patients with IgA nephropathy. clusion criteria and details of both the main and
SGLT2 inhibitor strata are described in the Sup-
plementary Appendix.
Me thods
Trial Design and Oversight Trial Procedures
The design of this phase 3, multinational, dou- Eligible patients were randomly assigned, in a 1:1
ble-blind, randomized, placebo-controlled trial ratio, to receive either atrasentan (0.75 mg once
has been published10 and is summarized in Fig- daily) or matching placebo. Randomization was
ure S1 in the Supplementary Appendix, available performed with the use of a central interactive
with full text of this article at NEJM.org. The trial Web-based response system and was stratified
was sponsored by Novartis. A steering committee according to geographic region (Asia vs. all other
of eight academic members and three sponsor regions) and urinary protein-to-creatinine ratio
employees was responsible for the design and over- (with protein measured in milligrams and cre-
2 n engl j med nejm.org
Atr asentan in Patients with IgA Nephropathy
atinine measured in grams) at screening (≥2000 out period. At all in-person trial visits, blood was
vs. <2000). All parties who are involved in the drawn for clinical chemical assessment. Twenty-
conduct of the trial remain unaware of the trial- four hour urine samples for assessment of the
group assignments, with the exception of the urinary protein-to-creatinine ratio and urinary
data and safety monitoring board and the team albumin-to-creatinine ratio were collected at base-
responsible for the conduct of the prespecified line and at weeks 6, 12, 24, and 36. In addition,
interim analysis; members of this team were first-morning void urine samples for assessment
precluded from further participation in any trial- of the urinary protein-to-creatinine ratio and uri-
related activity after receiving access to unblind- nary albumin-to-creatinine ratio and vital-sign
ed data. measurements were collected throughout the trial.
In-person trial visits were performed at screen- Proteinuria and clinical chemical measurements,
ing, baseline (day 1), and weeks 2, 4, 6, and 12, including the serum creatinine level, were per-
then every 12 weeks thereafter (such visits will formed in a central laboratory. The eGFR was
continue until week 132). After the week 132 calculated with the use of the Chronic Kidney
visit, atrasentan or placebo will be discontinued Disease Epidemiology Collaboration creatinine
and the patients will proceed to a 4-week wash- equation.11
653 Patients were assessed for eligibility
249 Were excluded

235 Did not meet eligibility criteria
14 Met eligibility criteria but did
not undergo randomization
404 Underwent randomization
64 Were included in the exploratory

SGLT2 inhibitor stratum
340 Were included in the main stratum

intention-to-treat population
First 270 underwent randomization for

interim analysis of primary outcome
135 Were assigned to receive atrasentan 135 Were assigned to receive placebo
10 Discontinued trial regimen 22 Discontinued trial regimen

1 Withdrew 10 Withdrew
3 Had adverse event 4 Had adverse event
6 Had other reason 8 Had other reason
4 Discontinued trial early 11 Discontinued trial early
124 Had primary-outcome data available 114 Had primary-outcome data available
at wk 36 at wk 36
169 Were included in the safety analysis 170 Were included in the safety analysis
Figure 1. Screening, Randomization, and Follow-up.

SGLT2 denotes sodium–glucose cotransporter 2.

Table 1. Demographic and Clinical Characteristics of the First 270 Patients in the Main Stratum.*
Atrasentan Placebo
Characteristic (N = 135) (N = 135)
Age — yr 45.7±12.9 44.1±11.0
Female sex — no. (%) 54 (40.0) 57 (42.2)
Race — no. (%)†
Asian 75 (55.6) 79 (58.5)
White 49 (36.3) 48 (35.6)
Black 4 (3.0) 1 (0.7)
Other 7 (5.2) 7 (5.2)
Geographic region
Asia 64 (47.4) 63 (46.7)
Latin America and the Caribbean 29 (21.5) 23 (17.0)
Northern America: Canada and United States 20 (14.8) 26 (19.3)
Europe 11 (8.1) 13 (9.6)
Oceania 11 (8.1) 10 (7.4)
Body-mass index‡ 27.05±5.44 27.66±6.46
Duration of disease — yr 5.14±5.41 6.14±6.04
Blood pressure — mm Hg
Systolic 125.4±13.3 122.9±12.3
Diastolic 79.6±9.8 78.7±9.0
Median total urinary protein excretion (IQR) — mg/day 1847.4 (1314.0–2775.9) 1851.0 (1328.9–2550.0)
24-Hour urinary protein-to-creatinine ratio§
Median (IQR) 1435.7 (1006.7–1988.6) 1429.2 (1100.9–1918.3)
Distribution — no. (%)
<1500 72 (53.3) 76 (56.3)
≥1500 63 (46.7) 59 (43.7)
Median 24-hour urinary albumin-to-creatinine ratio (IQR)¶ 1051.3 (769.2–1485.8) 1059.3 (770.2–1480.8)
Estimated glomerular filtration rate
Mean — ml/min/1.73 m2 58.28±23.75 59.49±24.42
Distribution — no. (%)
≤45 ml/min/1.73 m2 54 (40.0) 53 (39.3)
>45–60 ml/min/1.73 m 2
25 (18.5) 28 (20.7)
>60 ml/min/1.73 m2 56 (41.5) 54 (40.0)
Hemoglobin level — g/dl 13.58±1.73 13.70±1.74
Use of RAS inhibitor at baseline — no. (%)
ARB only 97 (71.9) 95 (70.4)
ACE inhibitor only 37 (27.4) 37 (27.4)
Use of diuretic at baseline — no./total no. (%) 21/134 (15.7)‖ 16/135 (11.9)
* Plus–minus values are means ±SD. A total of 340 patients were recruited into the main stratum; shown are the char-
acteristics of the first 270 patients who completed the week 36 visit (intention-to-treat population). Atrasentan was ad-
ministered at a dose of 0.75 mg per day. Percentages may not total 100 because of rounding. ACE denotes angiotensin-
converting enzyme, ARB angiotensin-receptor blocker, IQR interquartile range, and RAS renin–angiotensin system.
† Race was reported by the patients. “Other” includes patients with multiple races and no races reported.
‡ The body-mass index is the weight in kilograms divided by the square of the height in meters.
§ Urinary protein was measured in milligrams, and urinary creatinine was measured in grams.
¶ Urinary albumin was measured in milligrams, and urinary creatinine was measured in grams.
‖ The percentage was calculated on the basis of the safety population.
Outcomes ed anemia, vasodilatation, hypotension, cardiac

The primary outcome to evaluate the efficacy of failure, and fluid retention.
atrasentan was the change in the urinary pro-
tein-to-creatinine ratio (based on 24-hour urine Statistical Analysis
collection) from baseline to week 36 after the The sample-size calculation indicated that 270
first 270 patients in the main stratum had un- patients in the main stratum would provide ap-
dergone the week 36 visit. The exploratory out- proximately 90% power with a two-sided alpha
come of the change in the urinary protein-to- of 0.01 to detect that the mean percentage change
creatinine ratio from baseline to week 36 in the in the urinary protein-to-creatinine ratio from
SGLT2 inhibitor stratum was also examined. baseline to week 36 was lower by at least 28 per-
Safety outcomes were any adverse events that centage points in the atrasentan group than in
emerged or worsened in severity after the initia- the placebo group (i.e., a natural log–transformed
tion of atrasentan or placebo, serious or severe treatment effect of 0.33), under the assumption
adverse events, and adverse events that led to of a standard deviation of 0.67 in the log-trans-
discontinuation of atrasentan or placebo. These formed urinary protein-to-creatinine ratio and a
outcomes were assessed in the entire main stra- 5% incidence of early discontinuation of the
tum, not just the first 270 patients. Adverse events trial before week 36. The primary analysis was
were coded according to the Medical Dictionary for conducted after 270 patients in the main stratum
Regulatory Activities (version 24.0). Because endo- of the intention-to-treat population had either
thelin-receptor antagonists may cause sodium completed the week 36 visit or discontinued the
and fluid retention, adverse events of special in- trial. The baseline value for urinary protein-to-
terest, identified with the use of Food and Drug creatinine ratio (on a natural log scale) was de-
Administration Medical Query categories, includ- fined as the mean of the two separate ratio results
A Change in 24-Hour Urinary Protein-to-Creatinine B Change in 24-Hour Urinary Protein-to-Creatinine Ratio at Weeks 6, 12, 24, and 36
Ratio at Week 36
−36.1 percentage points
(95% CI, −44.6 to −26.4); P<0.001
10 10 −3.1%
Percentage Change from Baseline
(95% Cl, −12.4 to 7.3)

0 0
Percentage Change from Baseline
Placebo
−10 −10
−3.1% (95% Cl,
−12.4 to 7.3) −20
−20
−38.1%
−30 Atrasentan
(95% CI, −43.9 to −31.7)
−30
−40
−40
−38.1% (95% CI, −50
−50 −43.9 to −31.7) 0 6 12 24 36
Weeks since Randomization
−60
Atrasentan Placebo No. of Patients
(N=124) (N=114) Placebo 132 129 130 126 114
Atrasentan 132 129 125 125 124
Figure 2. Change in 24-Hour Urinary Protein-to-Creatinine Ratio (Primary Outcome).

The primary outcome was the change in the 24-hour urinary protein-to-creatinine ratio from baseline to week 36. The prespecified inter-
im analysis involved the first 270 patients in the main stratum (135 patients in each group). Data on the urinary protein-to-creatinine
ratio at week 36 were available for 124 patients in the atrasentan group and 114 patients in the placebo group. Panel A shows the geo-
metric least-squares mean percentage change from baseline in the urinary protein-to-creatinine ratio at week 36 as well as the geomet-
ric least-squares mean between-group difference. Panel B shows the geometric least-squares mean percentage change in the urinary
protein-to-creatinine ratio from baseline at weeks 6, 12, 24, and 36. A total of 3 patients in each group had no postbaseline data for the
urinary protein-to-creatinine ratio; these patients were excluded from the number of patients at baseline. I bars indicate 95% confidence
intervals in Panel A and standard errors in Panel B.

A Change in Systolic and Diastolic Blood Pressure

140
130 Systolic Blood Pressure

Placebo
120 Atrasentan
Mean Value (mm Hg)

110
100
90
Diastolic Blood Pressure
80 Placebo
Atrasentan
70
60
0
0 2 4 6 12 24 36
Trial Week
No. of Patients
Placebo 170 165 161 167 166 157 123
Atrasentan 169 162 164 165 161 154 129
B Change in Body Weight

90
85
80
Mean Value (kg)
Placebo
75 Atrasentan
70
65
60
0
0 2 4 6 12 24 36
Trial Week
No. of Patients
Placebo 170 165 161 167 166 156 123
Atrasentan 169 162 164 165 161 154 129
C Change in B-Type Natriuretic Peptide Level

50
45
40
Mean Value (pg/ml)
35
30
25 Atrasentan
20
Placebo
15
10
5
0
0 4 24 36
Trial Week
No. of Patients
Placebo 170 155 152
Atrasentan 169 156 151
Figure 3 (facing page). Blood Pressure, Body Weight,

medications — were not included in the pri-
and B-Type Natriuretic Peptide Levels. mary analysis.
Shown are mean values from baseline to week 36 in The primary outcome was tested at a signifi-
systolic and diastolic blood pressure (Panel A) and cance level of 0.01 (two-sided) at the interim
body weight (Panel B) and the mean value from base- analysis. Secondary outcomes will be tested in
line to week 24 in B-type natriuretic peptide (Panel C) hierarchical fashion at the final analysis after all
in the main stratum of the trial. Laboratory reference
ranges for B-type natriuretic peptide according to age
the patients in the main stratum have completed
are as follows: 0 to 44 years, 2.7 to 33.3 pg per millili- the double-blind portion of the trial (see the
ter; 45 to 54 years, 2.7 to 46.7 pg per milliliter; 55 to Supplementary Appendix). The exploratory out-
64 years, 2.7 to 53.2 pg per milliliter; 65 to 74 years, come of the change in the urinary protein-to-
2.7 to 72.3 pg per milliliter; and older than 74 years, creatinine ratio from baseline to week 36 in the
2.7 to 176 pg per milliliter. I bars indicate 95% confi-
dence intervals.
SGLT2 inhibitor stratum was analyzed with the
use of the same model as in the primary analy-
sis. No hypothesis testing was performed.
from 24-hour urine samples collected within 21 Safety was assessed by collecting data on all
days of each other and before the first dose of adverse events, serious adverse events, and ad-
atrasentan or placebo. If one of the 24-hour verse events of special interest that occurred from
urine samples that was collected for the baseline the first dose up to 30 days after the last dose,
assessment was missing, the single value for 24- unless otherwise specified. Statistical analyses
hour urinary protein-to-creatinine ratio was used were conducted with the use of SAS software,
for the baseline assessment. version 9.4.
The primary outcome was the change in the
24-hour urinary protein-to-creatinine ratio from R e sult s
baseline to week 36. The analysis of the primary
outcome used a repeated-measures model. The Trial Patients
model included the change from baseline in the The trial was conducted at 133 sites in 20 coun-
natural log of the urinary protein-to-creatinine tries, and patients underwent randomization from
ratio at each postbaseline measurement through March 2021 through April 2023. Overall, 653
week 36 as outcomes. The model also included patients were screened, of whom 404 met the
the fixed effects of trial group, visit, and interac- inclusion criteria and were randomly assigned to
tion between trial group and visit, with covari- receive atrasentan (0.75 mg per day) or placebo;
ates of the baseline natural log of the urinary 340 patients were recruited into the main stratum
protein-to-creatinine ratio and baseline eGFR as and 64 into the SGLT2 inhibitor stratum. Among
continuous variables and the randomization strati- the first 270 patients in the main stratum who
fication factor of geographic region (Asia vs. all completed 36 weeks of the trial, 135 underwent
other regions). The covariance structure was as- randomization in each trial group. A total of 10
sumed to be unstructured and the same in each patients (7.4%) in the atrasentan group and 22
trial group. The log-transformed change in the (16.3%) in the placebo group discontinued the
urinary protein-to-creatinine ratio from baseline trial regimen; 4 patients (3.0%) and 11 (8.1%), re-
was estimated with the use of least-squares means. spectively, discontinued the trial (Fig. 1).
To facilitate the interpretation of the result, the The baseline characteristics of the patients
least-squares means estimate was back-exponen- were well balanced between the two groups
tiated to obtain the equivalent geometric mean (Table 1). The mean age of the patients was 44.9
percent change. Missing data were assumed to be years, and 41.1% were women. The mean dura-
missing at random. Data on the urinary protein- tion of IgA nephropathy was 5.6 years, the mean
to-creatinine ratio that were collected after an eGFR was 58.9 ml per minute per 1.73 m2, and
intercurrent event — defined as kidney trans- the median 24-hour urinary protein-to-creati-
plantation, long-term dialysis, use of SGLT2 in- nine ratio was 1433. Most patients (98.5%) were
hibitors, or use of prohibited systemic gluco- using an ACE inhibitor or ARB (Table 1). The
corticoids and other restricted or prohibited recruited patients were representative of the gen-

eral population of patients with IgA nephropathy group (Fig. 3A). At week 36, the mean change in
and were consistent with the patients involved in body weight was –0.2±2.8 kg in the atrasentan
other trials (Table S1). group and –0.1±3.0 kg in the placebo group
(Fig. 3B). At week 24, the mean change in the
Primary Outcome BNP level was 4.0±23.9 pg per millimeter in the
In the atrasentan group, the geometric mean uri- atrasentan group and –0.6±18.8 pg per milliliter
nary protein-to-creatinine ratio changed from in the placebo group (Fig. 3C).
1450.2 at baseline to 882.2 at week 36 (−38.1%; The percentage of patients with adverse events
95% confidence interval [CI], −43.9 to −31.7). In was similar in the atrasentan group (82.2%) and
the placebo group, the geometric mean urinary the placebo group (84.7%). Similarly, the per-
protein-to-creatinine ratio changed from 1484.3 centage of patients with severe or serious ad-
at baseline to 1374.8 at week 36 (−3.1%; 95% CI, verse events and the percentage of patients who
−12.4 to 7.3). These findings corresponded to a discontinued the trial regimen owing to an ad-
geometric mean between-group difference of verse event did not differ between the trial
−36.1 percentage points (95% CI, −44.6 to −26.4; groups (Table 2). Of the most common adverse
P<0.001) (Fig. 2A). The reduction in the urinary events, nasopharyngitis, peripheral edema, ane-
protein-to-creatinine ratio in the atrasentan group mia, pyrexia, and upper respiratory tract infec-
was evident at week 6 and sustained through tion were more common in the atrasentan group
week 36 (Fig. 2B. The only intercurrent events than in the placebo group. Some adverse events
that were observed and that led to censoring of of special interest — anemia, fluid retention,
data on the urinary protein-to-creatinine ratio in and vasodilatation or hypotension — were more
the primary analysis were initiation of restricted commonly reported with atrasentan than with
medication, which occurred in four patients placebo (Table 2). However, these events did not
(3.0%) in the atrasentan group and in seven pa- lead to discontinuation of the trial regimen, and
tients (5.2%) in the placebo group. A prespeci- no patient reporting anemia received a blood
fied sensitivity analysis including all values for transfusion. There were no reports of cardiac
urinary protein-to-creatinine ratio regardless of failure, severe edema, or death during the trial.
intercurrent events showed a geometric mean During the first 36 weeks of the treatment pe-
between-group difference (atrasentan vs. placebo) riod, 10 patients (5.9%) in each trial group initi-
of −36.7 percentage points (95% CI, −44.8 to ated diuretics.
−27.3). The effect of atrasentan as compared with
placebo was consistent across prespecified sub-
Discussion
groups (Fig. S2).
In this prespecified interim analysis of an ongoing
Exploratory Efficacy Outcome phase 3 clinical trial involving patients with IgA
Among 29 patients in the SGLT2 inhibitor stra- nephropathy, 36 weeks of treatment with atrasen-
tum who completed 36 weeks of the trial, the tan (0.75 mg per day) as compared with placebo
geometric mean percentage change in the urinary reduced the urinary protein-to-creatinine ratio by
protein-to-creatinine ratio from baseline was 36.1 percentage points (P<0.001). This benefit is
−39.6% (95% CI, −54.1 to −20.4) in the atrasen- clinically meaningful, especially in the context
tan group (14 patients) and −3.4% (95% CI, of a high-risk trial population (patients had a
−26.3 to 26.5) in the placebo group (15 patients). total urinary protein excretion of ≥1 g per day at
These findings corresponded to a geometric mean baseline, despite appropriate supportive care) and
between-group difference of −37.4 percentage a reassuring safety and side-effect profile. Ex-
points (95% CI, −57.2 to −8.5) (Fig. S3). amination of the longer-term efficacy of atrasen-
tan in reducing the decline in the eGFR as a key
Safety Outcomes secondary outcome is ongoing and will be pre-
At week 36, the mean (±SD) change in blood pres- sented after all the patients in the main stratum
sure from baseline was −3.94±11.90 mm Hg have completed the double-blind treatment pe-
(systolic) and −4.25±8.96 mm Hg (diastolic) in the riod of 136 weeks.
atrasentan group and 2.67±12.25 mm Hg and The effects of atrasentan were observed in a
2.25±10.70 mm Hg, respectively, in the placebo population of patients with IgA nephropathy who
Table 2. Adverse Events in the Main Stratum.*
Atrasentan Placebo
Event (N = 169) (N = 170)
no. of patients (%)

Any adverse event 139 (82.2) 144 (84.7)
Adverse events occurring in >5% of the patients in either group
Covid-19 35 (20.7) 37 (21.8)
Nasopharyngitis 17 (10.1) 10 (5.9)
Peripheral edema 15 (8.9) 11 (6.5)
Anemia 11 (6.5) 2 (1.2)
Pyrexia 11 (6.5) 7 (4.1)
Upper respiratory tract infection 11 (6.5) 9 (5.3)
Headache 10 (5.9) 11 (6.5)
Muscle spasms 10 (5.9) 4 (2.4)
Cough 9 (5.3) 4 (2.4)
Diarrhea 9 (5.3) 7 (4.1)
Dizziness 9 (5.3) 6 (3.5)
Hypotension 9 (5.3) 6 (3.5)
Nausea 9 (5.3) 7 (4.1)
Back pain 8 (4.7) 15 (8.8)
Influenza 6 (3.6) 10 (5.9)
Hypertension 2 (1.2) 12 (7.1)
Any serious adverse event 10 (5.9) 11 (6.5)
Any severe adverse event 12 (7.1) 10 (5.9)
Any adverse event leading to discontinuation of atrasentan or placebo 6 (3.6) 6 (3.5)
Adverse event of special interest†
Anemia‡ 14 (8.3) 4 (2.4)
Cardiac failure 0 0
Fluid retention 19 (11.2) 14 (8.2)
Vasodilatation or hypotension 10 (5.9) 7 (4.1)
Any adverse event of special interest 38 (22.5) 24 (14.1)
Any serious adverse event of special interest 0 0
Any moderate or severe adverse event of special interest 10 (5.9) 11 (6.5)
Any adverse event of special interest leading to discontinuation of atrasen- 0 0
tan or placebo
* Shown are adverse events that emerged or worsened in severity after the initiation of atrasentan or placebo. Covid-19
denotes coronavirus disease 2019.
† Adverse events of special interest are shown according to Food and Drug Administration Medical Query category.
‡ No patient with anemia received a blood transfusion.
were treated according to current clinical-practice patients with IgA nephropathy.12 Sparsentan did
guidelines, including maximum tolerated doses not significantly reduce the rate of eGFR decline
of RAS inhibitors and lifestyle modification. These over a period of 2 years. However, the change in
additive effects are consistent with the findings of the eGFR from baseline to the end of the 4-week
an earlier report on sparsentan (a dual blocker of washout period was significantly reduced with
endothelin receptor and angiotensin receptor) in sparsentan.13

During the conduct of the present trial, pub- IgA nephropathy. Adverse events involving anemia
lished post hoc analyses of two clinical trials were more frequently reported with atrasentan
showed the kidney-protective effects of SGLT2 than with placebo. This effect has been observed
inhibitors in patients with IgA nephropathy.14,15 with other endothelin-receptor antagonists in
In our interim analysis, a separate exploratory stra- which hemodilution has been thought to be a
tum of patients who were receiving stable doses potential mechanism.19 At the end of the trial,
of RAS and SGLT2 inhibitors was therefore add- patients can continue atrasentan in an open-label
ed. Exploratory interim analyses of that stratum extension study that will allow longer-term safety
showed similar effects of atrasentan in reducing and efficacy monitoring.
proteinuria in the SGLT2 inhibitor stratum as com- The present prespecified interim analysis
pared with the main stratum. These initial data showed the efficacy of atrasentan using a sur-
from the exploratory SGLT2 inhibitor stratum rogate outcome. Although the final results of
must be interpreted with caution, given the small the ALIGN trial will be needed to confirm that
numbers of patients. With a growing number of the proteinuria reduction seen with atrasentan
approved therapies, which now include an oral, translates to a reduction in eGFR decline, there
targeted-release budesonide formulation (Nefe- is growing confidence in the urinary protein-to-
con) as well as sparsentan and iptacopan, there creatinine ratio as a surrogate biomarker in IgA
is an opportunity to deliver a multitargeted treat- nephropathy.20,21
ment regimen to simultaneously inhibit the key Our trial has certain limitations. Although we
pathogenic pathways in IgA nephropathy, in- enrolled a representative cohort of patients with
cluding endothelin system activation, to possibly IgA nephropathy at high risk for kidney failure,
slow or halt the progressive loss of kidney func- the results cannot be generalized to patients with
tion of patients with IgA nephropathy.13,16,17 a total urinary protein excretion of less than 1 g
The current trial showed that atrasentan was per day. In addition, Black patients were under-
associated with a favorable safety profile. Previ- represented, which limits generalizability to these
ous studies involving persons with chronic kidney patients. Finally, the data presented here are lim-
disease and heart failure have shown that endo- ited to the primary outcome at the time of the
thelin-receptor antagonists can precipitate or 9-month interim analysis.
worsen preexisting heart failure, leading to pre- In this prespecified interim analysis of a multi-
mature termination of at least one trial involving national, randomized, controlled trial, atrasentan
patients with type 2 diabetes and chronic kidney reduced proteinuria after 36 weeks of treatment
disease with another endothelin-receptor antag- without apparent safety issues in patients with IgA
onist.18 Although there was a numerical imbal- nephropathy at high risk for progression to kidney
ance in adverse events involving fluid retention failure.
in our trial, none of them led to discontinuation
Supported by Novartis.
of the trial regimen. No cases of heart failure were Disclosure forms provided by the authors are available with
reported, and instances of peripheral edema were the full text of this article at NEJM.org.
generally balanced between the trial groups. In A data sharing statement provided by the authors is available
with the full text of this article at NEJM.org.
addition, changes in body weight and BNP levels We thank all the patients for their participation in the
over time did not differ substantially between the ALIGN trial, and Cathy McDonnell and Shivani Vadapalli,
atrasentan and placebo groups. The above reported Global Business Services, Novartis, for editorial support with
a earlier version of the manuscript, under the direction of the
data reflect the low risk of clinically important authors and in accordance with Good Publication Practice
fluid retention in this population of patients with guidelines (www.ismpp.org/gpp-2022).
References
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The n e w e ng l a n d j o u r na l of m e dic i n e

Atrasentan in Patients with IgA Nephropathy

n engl j med﻿﻿ nejm.org﻿ 1

2 n engl j med﻿﻿ nejm.org﻿

653 Patients were assessed for eligibility

249 Were excluded

404 Underwent randomization

64 Were included in the exploratory

340 Were included in the main stratum

First 270 underwent randomization for

10 Discontinued trial regimen 22 Discontinued trial regimen

Figure 1. Screening, Randomization, and Follow-up.

n engl j med﻿﻿ nejm.org﻿ 3

4 n engl j med﻿﻿ nejm.org﻿

Outcomes ed anemia, vasodilatation, hypotension, cardiac

(95% Cl, −12.4 to 7.3)

Figure 2. Change in 24-Hour Urinary Protein-to-Creatinine Ratio (Primary Outcome).

n engl j med﻿﻿ nejm.org﻿ 5

A Change in Systolic and Diastolic Blood Pressure

130 Systolic Blood Pressure

Mean Value (mm Hg)

B Change in Body Weight

C Change in B-Type Natriuretic Peptide Level

6 n engl j med﻿﻿ nejm.org﻿

Figure 3 (facing page). Blood Pressure, Body Weight,

n engl j med﻿﻿ nejm.org﻿ 7

8 n engl j med﻿﻿ nejm.org﻿

Table 2. Adverse Events in the Main Stratum.*

no. of patients (%)

n engl j med﻿﻿ nejm.org﻿ 9

10 n engl j med﻿﻿ nejm.org﻿

n engl j med﻿﻿ nejm.org﻿ 11

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