Original Article

Phase 2 Trial of Cemdisiran in Adult Patients with IgA

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Nephropathy: A Randomized Controlled Trial

Jonathan Barratt ,1 Adrian Liew ,2 See Cheng Yeo ,3 Anders Fernström ,4 Sean J. Barbour,5 C. John Sperati ,6
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Russell Villanueva ,7 Ming-Ju Wu ,8 Dazhe Wang,9 Anna Borodovsky,9 Prajakta Badri ,9 Elena Yureneva,9
Ishir Bhan ,9 and Daniel Cattran10; on behalf of the Cemdisiran Phase 2 Study Investigators and Collaborators*

Abstract
Background IgA nephropathy is the most common primary GN. Clinical features of IgA nephropathy Due to the number of
include proteinuria, which is the strongest known surrogate of progression to kidney failure. Complement contributing authors,
pathway activation is a critical driver of inflammation and tissue injury in IgA nephropathy. Cemdisiran the affiliations are
listed at the end of this
is an investigational RNA interference therapeutic that suppresses hepatic production of complement article.
component 5 (C5), thereby potentially reducing proteinuria in IgA nephropathy. We evaluated the
efficacy and safety of cemdisiran in adult patients with IgA nephropathy at high risk of kidney disease Correspondence:
Dr. Jonathan Barratt,
progression. Department of
Cardiovascular
Methods In this phase 2, 36-week, double-blind study, adult patients with IgA nephropathy and urine protein Medicine, University
$1 g/24 hours were randomized (2:1) to subcutaneous cemdisiran 600 mg or placebo every 4 weeks in of Leicester, University
combination with the standard of care. The primary end point was percentage change from baseline at week 32 Road, Leicester LE1
7RH, United Kingdom.
in urine protein-to-creatinine ratio (UPCR) measured by 24-hour urine collection. Additional end points included Email: jb81@leicester.
change from baseline in UPCR measured by spot urine, serum C5 level, and safety assessments. ac.uk

Results Thirty-one patients were randomized (cemdisiran, N522; placebo, N59). Cemdisiran-treated patients
had a placebo-adjusted geometric mean change in 24-hour UPCR of –37.4% (cemdisiran-adjusted geometric
mean ratio to baseline [SEM], 0.69 [0.10]) at week 32. Spot UPCR was consistent with 24-hour UPCR placebo-
adjusted change of –45.8% (cemdisiran-adjusted geometric mean ratio to baseline [SEM], 0.73 [0.11]). Mean (SD)
change in serum C5 level from baseline at week 32 was –98.7% (1.2) with cemdisiran and 25.2% (57.7) with
placebo. Over 36 weeks, most adverse events were mild or moderate and transient; the most common adverse
event after cemdisiran treatment was injection-site reaction (41%).

Conclusions These findings indicate that treatment with cemdisiran resulted in a reduction of proteinuria at week
32 and was well tolerated.
CJASN ▪: 1–11, 2024. doi: https://doi.org/10.2215/CJN.0000000000000384

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Introduction defined as mean $1 g/24 hours, 7 is a strong risk

IgA nephropathy is the most common type of biopsy-
proven GN,1,2 affecting at least 2.5 of 100,000 individ-
uals annually.1 Racial and ethnic variations have been
observed, with significantly higher rates of IgA ne-
phropathy in East and Southeast Asia compared with
Europe and North America.2–4
In patients with IgA nephropathy, galactose-
deficient IgA1 and anti-galactose–deficient IgA1
antibody immune complexes deposit in the kidney
mesangium, activating the complement system and
leading to chronic inflammation. This results in fi-
brosis and, ultimately, loss of kidney function.5,6
Clinical features of IgA nephropathy include hema-
turia, proteinuria, impaired kidney function, and
hypertension. 3 Persistent high-grade proteinuria,
factor of progression, with 25% of patients experi-
encing kidney failure within 7.5 years. 8
Treatment options for IgA nephropathy are cur-
rently limited to strategies that reduce prote-
inuria, slow development of fibrosis, and control
hypertension.3,9 Renin–angiotensin–aldosterone sys-
tem inhibitors are now the standard of care, with an
evolving role for sodium-glucose cotransporter-2 in-
hibitors.10 Immunosuppression may be considered
but is limited by variable efficacy and toxicities.11
There remains an unmet need for effective, well-
tolerated, disease-specific therapies.
Evidence suggests that IgA nephropathy pathogen-
esis is related to activation of complement pathways,
with the terminal pathway including complement

www.cjasn.org Vol ▪ ▪▪▪, 2024 Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology. 1
 2 CJASN
component (C) 5b–9 (membrane attack complex [MAC])
playing a dominant role in driving kidney injury.12 Mark-
ers of complement activation may identify patients with
IgA nephropathy likely to progress to significant kidney
impairment.13 Therefore, complement proteins represent
potential therapeutic targets for IgA nephropathy. Cem-
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disiran is an investigational, subcutaneously administered
RNA interference (RNAi) therapeutic in development for
the treatment of complement-mediated diseases.14 Cem-
disiran, comprising a small interfering RNA covalently
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linked to an N-acetylgalactosamine ligand, is designed to
enable reduction of hepatic complement component 5 (C5)
mRNA. C5 is the final protein in the complement cascade
before formation of the MAC; inhibition of C5 production
is expected to reduce generation of anaphylatoxin C5a and
the MAC, thereby decreasing cellular injury and tissue
inflammation in IgA nephropathy, regardless of whether
the complement cascade is activated by the classical, al-
ternative, or lectin pathway.15 Cemdisiran demonstrated
rapid and robust C5 reduction with few adverse events
in a phase 1 study.14 We present phase 2 study results
evaluating the effect of cemdisiran on proteinuria in adult
patients with IgA nephropathy who excrete .1 g of pro-
tein per day despite standard of care.
Methods
Study Design and Treatment
In this phase 2, 36-week, randomized, double-blind,
placebo-controlled, global, multicenter study, patients
were randomly assigned (2:1, using permuted blocks of
three) to receive subcutaneous cemdisiran 600 mg or pla-
cebo every 4 weeks in combination with the standard of
care. Randomization was stratified by average baseline
urine protein levels ($1 g/24 hours and ,2 g/24 hours
versus $2 g/24 hours). The study drug was administered
under investigator supervision or at a location other than
the study site (e.g., patient’s home) by a healthcare pro-
fessional. After the 36-week, double-blind period, patients
could enter a 156-week open-label extension. Further details
of the study design are included in Supplemental Figure 1,
and full details on randomization and blinding are included
in the Supplemental Appendix.
The study protocol and amendments were approved by
the relevant institutional review board or independent
ethics committee, as appropriate. Written informed con-
sent was obtained from all patients, and the study was
conducted in accordance with all applicable regulatory
requirements, the current guidelines of Good Clinical
Practice, and the principles that have their origin in the
Declaration of Helsinki. The authors who had access to the
data attest to their accuracy and completeness and the
fidelity of the trial to the protocol. All investigators, their
institutions, and the sponsor maintained data confidenti-
ality throughout the trial.
Study Population
Eligible patients were aged 18–65 years with a clinical
diagnosis of primary IgA nephropathy, demonstrated
by kidney biopsy performed within 60 months of
screening, and receiving stable, maximum-allowed or
‐tolerated angiotensin-converting enzyme inhibitor or
angiotensin receptor blocker for $3 months before run-
in. Patients provided two 24-hour urine collections 2
weeks before randomization to confirm their eligibi-
lity after the run-in period. Patients had mean urine
protein $1 g/24 hours at screening and at the end of the
run-in period. Hematuria was also confirmed, as defined
by $10 red blood cells per high-powered field by mi-
croscopy or a positive urine dipstick (21 [moderate] and
above) at screening.
Key exclusion criteria included concomitant significant
kidney disease other than IgA nephropathy, secondary eti-
ologies of IgA nephropathy, and an eGFR ,30 ml/min/
1.73 m2 2 weeks before randomization. Steroids or other
immunosuppressive therapies were not permitted within
6 months before randomization.
Full inclusion and exclusion criteria are listed in the
Supplemental Appendix.
End Points
The primary end point was percentage change from
baseline in urine protein-to-creatinine ratio (UPCR) mea-
sured by 24-hour urine collection at week 32 of treatment.
Secondary efficacy end points assessed at week 32 were
change from baseline in UPCR measured by spot urine,
percentage change from baseline in 24-hour urine protein
(g/24 hours), percentage of patients with partial clinical
remission (urine protein ,1.0 g/24 hours), percentage of
patients with .50% reduction in 24-hour urine protein, and
change from baseline in hematuria (measured by urine
dipstick using the light reflectance spectroscopy method).
Twenty-four–hour urine samples for determination of pro-
teinuria were analyzed by a central laboratory. Exploratory
end points included change from baseline in eGFR at week
32 and eGFR slope over the course of the study. Blood and
urine samples for these kidney function assessments were
collected before cemdisiran administration on dosing days,
if applicable.
The Oxford MEST-C classification, a histopathologic
tool assessing mesangial hypercellularity (M), endocapil-
lary hypercellularity (E), segmental glomerulosclerosis (S),
tubular atrophy/interstitial fibrosis (T), and cellular/
fibrocellular crescents (C),16 was documented at baseline
from pathology reports. In addition, the degree of com-
plement staining was also documented from pathology
reports, if available.
The pharmacodynamic effect of cemdisiran was mea-
sured every 4 weeks by the change from baseline in serum
C5, complement alternative pathway, and complement
classical pathway activity levels as quantified by the Wie-
slab enzyme-linked immunosorbent assays.17
Safety and tolerability assessments included the type,
incidence, and severity of adverse events that occurred
during the treatment period, classified by the Medical Dic-
tionary for Regulatory Activities System Organ Class and
Preferred Term. Clinical laboratory parameters and vital
signs were measured throughout.
Statistical Analyses
The sample size calculation was based on the precision of
the estimate of treatment effects for the primary end point
(UPCR measured in 24-hour urine at week 32) and was not
 CJASN ▪: 1–11, ▪▪▪, 2024
powered to detect between-group differences. At least 27
patients were planned for 2:1 randomization (cemdisiran:-
placebo). The geometric mean ratio of UPCR at week 32 to
baseline is statistically equivalent to the mean of the change
from baseline in logarithm of UPCR; therefore, the effect
size of the study was defined as the difference of change
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from baseline between cemdisiran and placebo in the log-
arithm of UPCR. On the basis of previous data,18 we as-
sumed that the geometric mean ratio of UPCR at week 32 to
baseline corresponded to a 12% and 50% reduction for the
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placebo and cemdisiran arms, respectively. This assumed
that sample sizes of 18 and nine patients in the cemdisiran
and placebo groups, respectively, would provide a width of
0.80 (60.4) for the 90% CI for treatment effect size estimate
(cemdisiran–placebo) in log scale. For details on study
blinding and how the randomization of patients was per-
formed, see the Supplemental Appendix.
The primary end point was analyzed using a restricted
maximum likelihood-based mixed-effect model for re-
peated measures approach, using all the data points be-
tween baseline and week 32. The mixed-effect model for
repeated measures was selected because of the continuous
nature of the data, repeated measurements, and for the
handling of missing data. The outcome variable was an-
alyzed in log scale and the model included fixed effects of
treatment, visit, interaction term of treatment and visit,
baseline 24-hour UPCR in log scale, and patient as a
random effect; unstructured working correlation was
used to model the within-patient error; the model-based
least-squares mean difference was then transformed back
to the original UPCR scale.
Changes from baseline in spot UPCR and 24-hour urine
protein at week 32 were analyzed similarly to the primary
end point. Percentage of patients with partial clinical re-
mission, and the between-group difference, were calculated
on the basis of the Wilson score method with continuity
correction. Percentage of patients with .50% reduction in
Randomized
N=31
Placebo
N=9
Treatment
discontinuation
n=1a (11.1%)
Completed double-blind
treatment period
n=8 (88.9%)
Received treatment in open-
label extension
n=8 (88.9%)
Figure 1. Randomization and patient disposition during the double-blind period of the study. aAfter treatment discontinuation, the patient
was withdrawn from the study because of death from coronavirus disease 2019, which occurred after the double-blind period (.28 days
after the last dose of the study drug) and was excluded from the safety reports as prespecified in the statistical analysis plan. No non-serious
adverse events led to treatment or study discontinuation.
Cemdisiran in Patients with IgA Nephropathy, Barratt et al. 3
24-hour urine protein, change from baseline in hematuria,
and eGFR at week 32 were reported descriptively. eGFR
slope was analyzed using a random coefficient model (see
Supplemental Appendix).
No formal statistical hypothesis testing was performed,
and no multiplicity adjustments were made. Additional
details regarding the primary and sensitivity analyses for
the efficacy end points, analyses for exploratory end
points, and handling of missing data are described in
the Supplemental Appendix.
Efficacy was analyzed in the modified intent-to-treat
population, defined as all patients who received any
amount of the study drug with baseline and at least one
post-baseline 24-hour UPCR assessment. Patients were
grouped by their assigned treatment at randomization.
Safety analyses were conducted in all patients who re-
ceived any amount of the study drug. Pharmacodynamic
assessments were measured in all patients who received a
dose of the study drug and had at least one post-dose
blood sample.
Results
Patients and Treatment
The first patient was randomized to study treatment
on September 30, 2019, and the last patient was ran-
domized to treatment on July 6, 2021. A total of 31
patients from 19 sites in nine countries were random-
ized to cemdisiran (N522) or placebo (N59) (Figure 1).
Twenty-one (95%) and eight (89%) patients in the cem-
disiran and placebo groups, respectively, completed the
36-week treatment period. One patient in the cemdisiran
group discontinued treatment because of death. One
patient in the placebo group discontinued treatment
during the double-blind period and was withdrawn
from the study because of death from coronavirus dis-
ease 2019, which occurred after the double-blind period;
Cemdisiran
N=22 Treatment
discontinuation and
study withdrawal due
to death
Completed double-blind n=1 (4.5%)
treatment period
n=21 (95.5%)
Received treatment in open-
label extension
n=20 (90.9%)
 4 CJASN

Table 1. Patient demographic and baseline disease characteristics

Placebo (N59) Cemdisiran (N522)

Age, yr, mean (SD) 38 (10) 41 (10)

Male, n (%) 3 (33) 13 (59)
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Race n (%)
Asian 4 (44) 12 (55)
White 4 (44) 8 (36)
Other/unreported 1 (11) 2 (9)
BMI, kg/m2, mean (SD) 26.8 (4.9) 30.4 (5.3)
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Time since diagnosis, yr, median (interquartile range) 2.5 (1.0–5.5) 1.8 (1.3–3.2)
Systolic BP, mm Hg, mean (SD) 116 (7) 125 (12)
Diastolic BP, mm Hg, mean (SD) 68 (13) 80 (8)
24-h urine protein, g/24 h, median (interquartile range) 2.80 (1.75–3.80) 2.00 (1.50–3.40)
24-hour UPCR, g/g, mean (SD) 1.97 (0.82) 1.55 (1.03)
eGFR, ml/min/ 1.73 m2, median (interquartile range) 47 (39–76) 68 (54–94)
Treatment with an ACEi, n (%)a,b 1 (11) 7 (32)
Treatment with an ARB, n (%)a,c 8 (89) 14 (64)

Oxford MEST-C Score, n (%) Placebo Cemdisirand

M
0 2 (22) 7 (32)
1 7 (78) 13 (59)
E
0 6 (67) 15 (68)
1 3 (33) 5 (23)
S
0 2 (22) 2 (9)
1 7 (78) 19 (86)
T
0 3 (33) 10 (45)
1 6 (67) 9 (41)
2 0 1 (5)
C
0 6 (67) 15 (68)
1 3 (33) 3 (14)
2 0 2 (9)

Complement C3 Staining, n (%) Placebo Cemdisirane

Strong 4 (44) 3 (14)

Medium 2 (22) 6 (27)
Weak 2 (22) 8 (36)
Absent 1 (11) 4 (18)

ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BMI, body mass index; C, cellular/fibrocellular
crescents; C3, complement component 3; E, endocapillary hypercellularity; M, mesangial hypercellularity; S, segmental
glomerulosclerosis; SGLT2, sodium-glucose cotransporter-2; T, tubular atrophy/interstitial fibrosis; UPCR, urine protein-to-
creatinine ratio.
a
Patients were on maximum-tolerated angiotensin-converting enzyme inhibitor or angiotensin receptor blocker; no patients were
previously treated with sodium-glucose cotransporter-2 inhibitors.
bOne patient in the placebo group was not receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker at

study baseline because of intolerance; however, their BP was well controlled with stable, optimal pharmacologic therapy, and all other
study eligibility criteria were met.
c
One patient in the cemdisiran group had prior combination of hydrochlorothiazide and telmisartan.
d
Missing cemdisiran values: M52, E52, S51, T52, C52.
e
Missing C3 staining for one patient in the cemdisiran group (4.5%).

this death was not included in the safety results for the
double-blind period. Twenty and eight patients entered
the open-label extension in the cemdisiran and placebo
groups, respectively.
Baseline demographics and clinical characteristics
were comparable between treatment groups (Table 1).
Most patients were male (cemdisiran: 59%; placebo:
33%) and Asian (52% Asian, 39% White, 3% other,
7% unreported), with a mean (SD) age of 41(10) and
38(10) years, respectively. At baseline, patients received
an angiotensin-converting enzyme inhibitor (25.8%) or an-
giotensin receptor blocker (71.0%). Median (interquartile
range) eGFR was 68 (54–94) and 47 (39–76) ml/min/
1.73 m2 in the cemdisiran and placebo groups,
respectively. Mean (SD) urine protein was 2.5 (1.5) g/24
hours in the cemdisiran group and 2.9 (1.3) g/24 hours in
the placebo group. MEST-C scores were broadly similar
across groups (Table 1). Information on IgA nephropathy
 CJASN ▪: 1–11, ▪▪▪, 2024 Cemdisiran in Patients with IgA Nephropathy, Barratt et al. 5

A 24-Hour UPCR Placebo Cemdisiran

1.8
Baseline (Standard Error of the Mean)
Adjusted Geometric Mean Ratio to

1.6
Change from baseline in
1.4 24-hour UPCR at week 32 (placebo):
in 24-Hour UPCR

+9.5% (–74.2)
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1.2 1.10 (0.26) Median change from baseline (range)

1.03 (0.20) 0.16 (–1.36, 1.16)
1.0
Change from baseline in
24-hour UPCR at week 32 (cemdisiran):
0.8 0.61 (0.08) 0.69 (0.10)
30% improvement –31.4% (–90.2)
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Median change from baseline (range)

0.6 –0.42 (–2.10, 1.08)
50% improvement

0.4
Baseline Week 16 Week 32
Study Visits
No. of Patients:
Placebo 9 9 8
Cemdisiran 22 21 22

B Spot UPCR
2.2
Baseline (Standard Error of the Mean)

2.0
Adjusted Geometric Mean Ratio to

1.8

1.6
in Spot UPCR

1.38 (0.12) 1.34 (0.14)

1.4 Change from baseline in
1.24 (0.09) 1.19 (0.16) 1.20 (0.11) 1.22 (0.16)
spot UPCR at week 32 (placebo):
1.2
1.04 (0.09) +34.4 (–86.1)
1.0 1.12 (0.14)
Change from baseline in
0.96 (0.11) 0.73 (0.12) 0.74 (0.11) 0.73 (0.11) spot UPCR at week 32 (cemdisiran):
0.8 30% improvement 0.66 (0.10) 0.69 (0.11) 0.72 (0.09)
–27.1 (–89.1)
0.6 0.67 (0.08)
50% improvement
0.4
Baseline Week 4 Week 8 Week 12 Week 16 Week 20 Week 24 Week 28 Week 32
Study Visits
No. of Patients:
Placebo 9 9 9 8 9 9 8 7 8
Cemdisiran 22 21 20 20 21 22 20 19 20

Figure 2. Change from baseline in 24-hour UPCR and spot UPCR over 32 weeks. (A) Change from baseline in 24-hour UPCR to week 32 in
patients treated with cemdisiran compared with placebo. The primary end point was a separate analysis using a mixed-effect model for
repeated measures, which showed a placebo-adjusted geometric mean percent change from baseline in 24-hour UPCR at week 32
of –37.4% (cemdisiran-adjusted geometric mean ratio to baseline [SEM], 0.69 [0.10]) in favor of cemdisiran. (B) Change from
baseline in spot UPCR compared with placebo to week 32 in patients treated with cemdisiran compared with placebo (secondary
end point). An additional analysis showed that after cemdisiran treatment, placebo-adjusted geometric mean change from baseline
in spot UPCR at week 32 was –45.8% (cemdisiran-adjusted geometric mean ratio to baseline [SEM], 0.73 [0.11]) (treatment
comparison and estimates were analyzed by a similar mixed-effect model for repeated measures as used for the primary end point).
CI, confidence interval; UPCR, urine protein-to-creatinine ratio.

and the representativeness of the study patients are provided Secondary End Points
in Supplemental Table 1. Mean (SD) spot UPCR decreased from 1.80 (1.19) to 1.49
(1.15) with cemdisiran and increased from 1.91 (1.18) to 2.21
Efficacy (1.01) with placebo at week 32. After cemdisiran treatment,
Primary End Point placebo-adjusted geometric mean change from baseline
Mean (SD) 24-hour UPCR decreased from 1.55 (1.03) to in spot UPCR was –45.8% (cemdisiran-adjusted geomet-
1.27 (1.02) g/g with cemdisiran and increased from 1.97 ric mean ratio to baseline [SEM], 0.73 [0.11]) at week 32
(0.82) to 2.03 (1.16) g/g with placebo at week 32. After (Figure 2B). Placebo-adjusted geometric mean change
cemdisiran treatment, placebo-adjusted geometric mean in 24-hour urine protein with cemdisiran was –36.2%
change from baseline in 24-hour UPCR was –37.4% (cem- (cemdisiran-adjusted geometric mean ratio to baseline
disiran-adjusted geometric mean ratio to baseline [SEM], [SEM], 0.67 [0.10]) (Supplemental Table 2).
0.69 [0.10]) at week 32 (Figure 2A). A higher proportion of patients receiving cemdisiran
A consistent treatment difference was observed in achieved partial clinical remission (urine protein
24-hour UPCR across predefined subgroups (age at the ,1.0 g/24 hours) at week 32 compared with placebo (cem-
time of consent, sex, race, baseline 24-hour urine protein, disiran: 22.7%; placebo: 0%). The proportion of patients
and baseline eGFR) (Supplemental Figure 2). achieving a .50% reduction in 24-hour urine protein at
 6 CJASN
Cemdisiran (N=22)
Hematuriaa Baseline
9/20
Large (45.0%)
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8/20
Moderate (40.0%)
Better
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3/20
Small (15.0%)
Negative 0
Figure 3. Hematuria grade from baseline to week 32 of the double-blind period (secondary end point). aHematuria was measured by urine
dipstick in the modified intent-to-treat population, using the light reflectance spectroscopy method. Hematuria category indicates reference
range from dipstick color change. The percentage of patients in each category at baseline and week 32 was calculated using the total
number of evaluable patients in the treatment group as the denominator.
week 32 was also higher with cemdisiran (22.7%) compared
with placebo (0%).
At week 32, 77.3% of cemdisiran-treated patients
showed a reduction from baseline in hematuria grade (dip-
stick analysis) compared with 22.2% of the placebo group;
no patient in either group demonstrated an increase in
hematuria (Figure 3).
Exploratory End Points
Mean (SD) change from baseline in eGFR at week 32
was –2.9 (11.1) ml/min/ 1.73 m2 for cemdisiran
compared with –6.3 (4.8) ml/min/ 1.73 m2 for placebo
(Supplemental Table 3). The estimated eGFR slope per
year was –6.76 for cemdisiran and –11.90 for placebo
(difference in slopes [cemdisiran2placebo]: 5.14; mean
[SD] for individual slope of placebo –11.90 [9.33] and
cemdisiran –6.76 [10.92], on the basis of week 36 data).
Pharmacodynamics
Mean (SD) serum C5 levels decreased from 109.50 (29.22)
to 1.30 (1.10) mg/l with cemdisiran and increased from
92.46 (27.46) to 98.16 (15.08) mg/l with placebo at week 32.
Cemdisiran-treated patients had a mean percentage change
(SD) in serum C5 of –98.7% (1.2) from baseline at week 32
compared with 25.2% (57.7) with placebo (Figure 4A).
Furthermore, mean percentage change (SD) in complement
activity, measured by serum complement alternative path-
way and complement classical pathway activity levels, was
–48.1% (22.6) and –76.9% (7.5) with cemdisiran, respec-
tively, and –1.5% (19.0) and 16.9% (13.5) with placebo,
respectively, at week 32 (Figure 4B and C).
Safety
During the 36-week, double-blind period, adverse events
occurred in 19 cemdisiran-treated patients (86%) and eight
placebo patients (89%); most adverse events were mild or
moderate (Table 2). Severe adverse events occurred in one
patient (5%) in the cemdisiran group and no patients in the
placebo group. One death occurred in the cemdisiran group
during the double-blind period due to cardiorespiratory
Placebo (N=9)
Week 32 Baseline Week 32
1/20 5/8 4/8
(5.0%) (62.5%) (50.0%)
4/20 2/8 2/8
(20.0%) (25.0%) (25.0%)
11/20 1/8 2/8
(55.0%) (12.5%) (25.0%)
4/20
(20.0%)
0 0
collapse, which occurred because of postoperative compli-
cations after elective cardiac surgery (a leak at the anasto-
mosis of a coronary artery bypass graft). This was
considered unrelated to the study drug and was both a
serious and severe adverse event. No other serious or severe
adverse events were observed in either group.
No other adverse events led to treatment or study dis-
continuation. Two treatment interruptions occurred in the
cemdisiran group (9%) in response to three adverse events,
reported for one patient (5%) who had urticaria and one
patient (5%) who had oropharyngeal pain and rhinorrhea.
In the placebo group, one treatment interruption occurred
because of atopic dermatitis.
The most common adverse events ($10% of patients) in
the cemdisiran group included injection-site reactions (ISRs)
(41%) and peripheral edema (14%); these occurred in the
placebo group in 22% and 11%, respectively. Most ISRs in
the cemdisiran group were mild, transient, and considered
related to the study drug; peripheral edema was reported as
mild and moderate and was considered unrelated to the
study drug.
No Neisseria spp., other encapsulated bacteria, or Asper-
gillus spp. infections were observed, and no deaths or
hospitalizations due to sepsis occurred. Infection-related
adverse events occurred at overall similar rates between
the cemdisiran and placebo groups and were mild to mod-
erate in severity.
Mild, transient elevations in alanine transaminase and
aspartate transaminase were observed in two cemdisiran-
treated patients (9%), which resolved without alteration of
dosing; no elevations in liver function tests were observed
in the placebo group (Table 3). There were no clinically
significant changes related to cemdisiran on liver function
tests, hematology, or kidney function, and no significant
changes were noted in BP in either treatment group.
Discussion
IgA nephropathy is characterized by high morbidity and
significant unmet clinical need, with 25% and 50% of
 CJASN ▪: 1–11, ▪▪▪, 2024 Cemdisiran in Patients with IgA Nephropathy, Barratt et al. 7

A C5 Placebo Cemdisiran
150
135

Mean C5 Protein Level (mg/L)

120
105
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90
75
60
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45
30
15
0
Baseline 4 8 12 16 20 24 28 32
Study Visit (Week)
No. of Patients:
Placebo 9 9 9 9 9 9 8 7 8
Cemdisiran 22 21 20 20 21 21 20 19 20

B Complement Alternative Pathway

40
Percentage Change from Baseline
in Serum Complement Alternative

20
Pathway (% Activity)

–20

–40

–60

–80

–100
0 4 8 12 16 20 24 28 32
Study Visit (Week)
No. of Patients:
Placebo 9 9 9 9 9 9 8 7 8
Cemdisiran 22 21 20 21 21 22 20 19 20

C Complement Classical Pathway

40
Percentage Change from Baseline
in Serum Complement Classical

20
Pathway (% Activity)

–20

–40

–60

–80

–100
0 4 8 12 16 20 24 28 32
Study Visit (Week)
No. of Patients:
Placebo 9 9 9 9 9 9 8 7 8
Cemdisiran 22 21 20 21 21 22 20 19 20

Figure 4. Serum levels of C5 protein and markers of complement activity in the cemdisiran and placebo groups over 32 weeks
(exploratory end points). (A) Mean C5 protein levels from baseline to week 32. (B) Percentage change from baseline in serum complement
 8 CJASN
Figure 4. (Continued) alternative pathway levels. (C) Percentage change from baseline in serum complement classical pathway levels. SD data
are shown in all figures (SD values from the mean C5 protein level values for the cemdisiran group [A] are too small to show clearly on the
figure from week 4 onward). C5, complement component 5.
patients progressing to kidney failure by 7.5 and 30 years,
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respectively.8,19 Current clinical practice guidelines suggest
glucocorticoid therapy for patients who remain at high
risk of progression to kidney failure, despite maximal sup-
WnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 03/21/2024
portive care.11 Targeted-release enteric budesonide was
the first IgA nephropathy–specific therapeutic approved,
on the basis of a 27% reduction in 24-hour UPCR at
9 months compared with placebo, although concerns for
glucocorticoid-induced toxicities remain.20
This study is the first to report use of an RNAi therapeutic
as a potential treatment of a glomerular disease. Cemdisiran
led to a 37.4% reduction in placebo-adjusted geometric mean
24-hour UPCR at week 32; this benefit was consistent across
predefined subgroups, including race. This represents a
clinically meaningful reduction in proteinuria with cem-
disiran at week 32, relative to placebo, with onset by week
16 sustained to week 32, although all analyses were hy-
pothesis generating. Further studies would be required to
validate the hypothesis. Spot UPCR was consistent with
24-hour UPCR, demonstrating a rapid reduction in pro-
teinuria by week 8 that remained stable over the study.
Robust data from 13 clinical trials have shown an associ-
ation between treatment-induced reductions in proteinuria
and favorable treatment effects, including slower progres-
sion to kidney failure and death.21 These data demonstrated
that proteinuria reduction is a clinically meaningful end
point in the management of IgA nephropathy and an ac-
cepted surrogate end point for reducing progression to
kidney failure.21,22 Proteinuria reduction amounting to par-
tial clinical remission was observed in 22.7% of cemdisiran-
treated patients while on current standard of care, compared
with no patients receiving placebo, suggesting that such a
reduction in proteinuria may lessen the adverse effect on
kidney function in patients with IgA nephropathy.
Preliminary data for eGFR suggested a slower decline in
cemdisiran-treated patients compared with placebo. These
Table 2. Adverse eventsa occurring during the double-blind period
Placebo (N59, Patient Years56.1)
Category
n (%)
Adverse event 8 (89)
Serious adverse event 0 (0)
Severe adverse event 0 (0)
Adverse event leading to study drug interruption 1 (11)
Adverse event leading to study drug discontinuation 0 (0)
Adverse event leading to study withdrawal 0 (0)
Deathb 0 (0)
a
Treatment-emergent adverse events, including events occurring or worsening on or after the first dose of the study drug, and through
28 days after the last dose.
b
All fatal adverse events are summarized, regardless of treatment-emergent classification.
data are consistent with the favorable effect of cemdisiran
on proteinuria, and observations in a larger study over a
longer time period may help clarify the magnitude and
precision of cemdisiran’s effect on eGFR. Hematuria was
reduced to a greater extent with cemdisiran compared with
placebo. Hematuria levels have been independently asso-
ciated with kidney disease progression, and hematuria re-
mission may be associated with improved kidney outcomes
in IgA nephropathy among patients with persistent pro-
teinuria, although this requires further investigation.23,24
Although BP control may affect proteinuria levels in pa-
tients with IgA nephropathy,25 BP was controlled and was
not different between treatment groups in this study.
Serum C5 levels were robustly lowered with cemdisiran
compared with placebo, evident at the first post-baseline
assessment at week 4. Reduction of C5 production led to
inhibition of complement activity, with a sustained and
significant decrease in complement alternative pathway
and complement classical pathway activity levels compared
with placebo, mirroring that of C5. Notably, the week 4
reduction in C5 preceded the week 8 reduction in spot
UPCR, highlighting that lowering C5 can have a rapid effect
on complement activation in the kidney. These results re-
inforce the therapeutic hypothesis that reduction of com-
plement activity by infrequent subcutaneous dosing of a
C5-lowering RNAi therapeutic may be an effective, targeted
treatment approach for IgA nephropathy as an alternative
or add-on to currently approved nonspecific therapies.
Most adverse events occurring in cemdisiran-treated pa-
tients were mild or moderate. The most common adverse
event was ISR, which occurred in 41% of cemdisiran-treated
patients. ISR is among the most common adverse events
reported with other subcutaneously administered small
interfering RNA–N-acetylgalactosamine conjugates and is
typically mild or moderate in severity. Transient effects on
liver function were also observed with cemdisiran in two
Cemdisiran (N522,
Patient Years515.3)
No. of Events/Exposure- No. of Events/Exposure-
Adjusted Event Rate per n (%) Adjusted Event Rate per
100 Patient Years 100 Patient Years
31/508.2 19 (86) 79/517.9
0 1 (5) 1/6.6
0 1 (5) 1/6.6
1/16.4 2 (9) 3/19.7
0 0 (0) 0
0 0 (0) 0
0 1 (5) 1/6.6
 CJASN ▪: 1–11, ▪▪▪, 2024 Cemdisiran in Patients with IgA Nephropathy, Barratt et al. 9

Glomerular Diseases, and Kidney International; and advisory or

Table 3. Most common adverse events occurring during the leadership role as Treasurer of International IgA Nephropathy
double-blind period Network. I. Bhan reports employment with AbbVie, Alnylam
Placebo Cemdisiran Pharmaceuticals Inc., and Bayer and ownership interest in Al-
(N59) (N522) nylam Pharmaceuticals Inc., Bayer, and Tesla. A. Borodovsky
Adverse Eventa
reports employment with, ownership interest in, and patents or
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n (%) n (%) royalties from Alnylam Pharmaceuticals Inc. D. Cattran reports

ISR 2 (22) 9 (41) consultancy for Alexion, Alnylam Pharmaceuticals Inc., Aurinia,
Edema peripheral 1 (11) 3 (14) Calliditis, Chemocentrx, Chinook Therapeutics, Chugai, Forsee,
Alanine aminotransferase 0 (0) 2 (9) Horizon, Reistone, Vera Therapeutics, and Zyversa Therapeutics;
WnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 03/21/2024

increased research funding from Alnylam Pharmaceuticals Inc.; honoraria

Aspartate aminotransferase 0 (0) 2 (9)
increased
Injection-site recall reaction 0 (0) 2 (9)
Coronavirus disease 2019 0 (0) 2 (9)
Oropharyngeal pain 0 (0) 2 (9)
Rash 0 (0) 2 (9)
Rhinorrhea 0 (0) 2 (9)
Nasopharyngitis 3 (33) 0 (0)
Back pain 2 (22) 0 (0)
ISR, injection-site reaction.
a
Most common adverse events (occurring in .1 patient in
either treatment group) during the double-blind period.
patients during the double-blind period, which did not
affect dosing.
Limitations of the study include the small number of
patients and the short treatment duration. These are con-
siderations for the interpretation of both the safety data, in
particular the incidence of infections, and the efficacy end
points, such as eGFR, in which changes may only become
apparent over a longer period. Studies in more diverse and
representative populations of patients with IgA nephropa-
thy are also warranted. The pharmacologic management of
IgA nephropathy continues to evolve, and this study was
conducted before the increasingly common use of sodium-
glucose cotransporter-2 inhibitors. However, the intention
of the study was to identify whether there was evidence of a
beneficial effect with cemdisiran on clinical markers of
disease activity in adult patients with IgA nephropathy,
which was indicated across a variety of end points.
In conclusion, in this 36-week, phase 2 study, treatment
with cemdisiran demonstrated a consistent benefit across
measures of proteinuria and was well tolerated in adults
with IgA nephropathy.
Disclosures
P. Badri reports employment with Alnylam Pharmaceuticals
Inc. and ownership interest in Alnylam Pharmaceuticals Inc.,
Dicerna Pharmaceuticals Inc., and Pyxis Oncology. S.J. Barbour
reports consultancy for Achillion, Alexion, BeiGene, BioCryst,
Chinook, Eledon, HIBio, Inception Sciences, Novartis, Pfizer,
Roche, Vera, and Visterra; research funding from Alexion, No-
vartis, and Roche; and honoraria from Kirin. J. Barratt reports
consultancy for Alebund, Alnylam Pharmaceuticals Inc., Alpine,
Argenx, Astellas, BioCryst, Calliditas, Chinook, Dimerix, HiBio,
Kira, Novartis, Omeros, Otsuka, Q32 Bio, Roche, Sanofi, Takeda,
Travere Therapeutics, Vera Therapeutics, Vifor, and Visterra;
research funding from Argenx, Calliditas, Chinook, Galapagos,
GlaxoSmithKline, Novartis, Omeros, Travere Therapeutics, and
Visterra; role on the Editorial Boards of CJASN, Clinical Science,
from Alexion, Calliditis, and Kyowa Hakko Kirin Co; advisory or
leadership role for Alnylam Pharmaceuticals Inc., Calliditis,
NephCure, SONG-GD, UpToDatem, and Vera; and other
interests/relationships with Aurinea, Dimerix, Novartis, and
Vera. A. Fernström reports consultancy for AO Pharma (adviser),
AstraZeneca, Bayer, Internetmedicin, Otsuka, TEVA (advisory
board), and Vifor Pharma (advisory board); ownership interest in
Alpha Helix, AstraZeneca, Diamyd Medical, Guard Therapeutics,
Hansa Biopharma, ISR Immune System Regulation, Kancera,
Medivir, Omeros Corporation, Oncopeptides, ProstaLund, S2
Medical, Spago Nanomedical, and Wntresearch; research funding
from AstraZeneca; and honoraria from AstraZeneca and Bayer. A.
Liew reports employment with The Kidney & Transplant Practice
Pte. Ltd; consultancy for Alnylam Pharmaceuticals Inc., Baxter
Healthcare, Bayer, Boehringer-Ingelheim, Chinook Therapeutics,
DaVita Inc., Eledon Pharmaceuticals, George Clinical, Kira Phar-
maceuticals, Otsuka Pharmaceuticals, and ProKidney; honoraria
from Alnylam Pharmaceuticals Inc., AstraZeneca, Baxter Health-
care, Bayer, Boehringer-Ingelheim, Chinook Therapeutics, and
Otsuka Pharmaceuticals; advisory or leadership role for Alnylam
Pharmaceuticals Inc., AstraZeneca, Bayer, Boehringer-Ingelheim,
Chinook Therapeutics, Eledon Pharmaceuticals, Kidney and Blood
Pressure Research (Editorial Board), Kidney International (Editorial
Board), Kidney Research and Clinical Practice (Editorial board), Kira
Pharmaceuticals, Nephrology Journal (Associate Editor), Otsuka,
Peritoneal Dialysis International (Editorial Board), and ProKidney;
consultancy agreements, advisory board memberships, and steer-
ing committee memberships with Alnylam Pharmaceuticals Inc.,
AstraZeneca, Baxter Healthcare, Bayer AG, BioCryst, Boehringer-
Ingelheim, Chinook Therapeutics, Dimerix Limited, Eledon,
George Clinical, GlaxoSmithKline, Kira, Otsuka, Prokidney, Vis-
terra Inc., and Zai Lab Co., Ltd.; data safety and monitoring
committee memberships with Dimerix Limited and Zai Lab Co.,
Ltd.; and speakers bureau for AstraZeneca, Baxter Healthcare,
Boehringer-Ingelheim, Chinook, and Otsuka. A. Liew reports other
interests or relationships as Chair, Asian-Pacific Society of Ne-
phrology Guideline on Diabetic Kidney Disease; Chair, ISN Renal
Disaster Preparedness Working Group; Secretary and Executive,
ISPD; Working Group Member, KDIGO Guideline on Diabetes
Management in CKD; and Working Group Member, KDIGO
Guideline Update on Glomerular Diseases. C.J. Sperati reports
consultancy for Alnylam Pharmaceuticals Inc., Disc Medicine, and
Q32 Bio; research funding from Alnylam Pharmaceuticals Inc.,
National Institutes of Health, and Novartis Pharmaceuticals;
honoraria from Alnylam Pharmaceuticals Inc.; advisory or lead-
ership role for Advances in Chronic Kidney Disease (Editorial Board),
American Board of Internal Medicine Nephrology Longitudinal
Assessment Committee, Current Hypertension Reports (Section Ed-
itor), DSMB participation for Alexion Pharmaceuticals, Alpine
Immune Sciences, Neurogene, Omeros Corporation, and National
Kidney Foundation Education Committee. R. Villanueva reports
 10 CJASN
advisory or leadership role for Boehringer‐Ingelheim regional
advisory board and Bayer local advisory board and speakers
bureau for AstraZeneca, Bayer, Boehringer‐Ingelheim, Globo
Asiatico, and Novartis. D. Wang was employed by Alnylam
Pharmaceuticals Inc. at the time of the study and reports stock
ownership of Alnylam Pharmaceuticals Inc. and ownership
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interest in Alnylam Pharmaceuticals Inc. M.-J. Wu reports
employment with Taichung Veterans General Hospital. E.
Yureneva reports employment with and ownership interest in
Alnylam Pharmaceuticals Inc.. The remaining author has nothing
WnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 03/21/2024
to disclose.
Funding
This work was supported by Alnylam Pharaceuticals and Re-
generon Pharmaceuticals.
Acknowledgments
The study was sponsored by Alnylam Pharmaceuticals and
designed by the sponsor in collaboration with the principal inves-
tigators. Data were collected by study investigators and analyzed
by the sponsor; interpretation of the data was performed by the
sponsor and the authors. Abstracts describing the results of this
study have been presented at the 18th European Meeting on
Complement in Human Disease (EMCHD), August 26–29, 2022,
Bern, Switzerland, and the American Society of Nephrology (ASN),
November 1–6, 2022, Orlando, Florida. We would like to thank all
the patients and their families for their participation in the cemdi-
siran phase 2 study, the cemdisiran phase 2 collaborators who are
listed in the Supplemental Appendix, and Julie Gray of Adelphi
Communications Ltd. (Macclesfield, United Kingdom) for medical
writing assistance (in accordance with Good Publication Prac-
tice guidelines).
Author Contributions
Conceptualization: Ishir Bhan, Anna Borodovsky, Adrian Liew,
Dazhe Wang.
Data curation: Dazhe Wang.
Formal analysis: Prajakta Badri, Ishir Bhan, Anna Borodovsky,
Dazhe Wang, Elena Yureneva.
Investigation: Sean J. Barbour, Jonathan Barratt, Daniel Cattran,
Anders Fernström, Adrian Liew, C. John Sperati, Russell Villa-
nueva, Ming-Ju Wu, See Cheng Yeo.
Methodology: Ishir Bhan, Anna Borodovsky, Dazhe Wang.
Validation: Prajakta Badri, Ishir Bhan, Anna Borodovsky, Dazhe
Wang, Elena Yureneva.
Writing – review & editing: Prajakta Badri, Sean J. Barbour,
Jonathan Barratt, Ishir Bhan, Anna Borodovsky, Daniel
Cattran, Anders Fernström, Adrian Liew, C. John Sperati,
Russell Villanueva, Dazhe Wang, Ming-Ju Wu, See Cheng
Yeo, Elena Yureneva.
Data Sharing Statement
Partial restrictions to the data and/or materials apply. Anony-
mized individual participant data that support these results would
be made available in a secure-access environment 12 months after
study completion and when the product and indication have been
approved for no less than 12 months in the United States and/or
the European Union. Access will be provided contingent upon the
approval of a research proposal and the execution of a data sharing
agreement. Requests for access to data can be submitted via the
website: www.vivli.org. Additional related documents, such as
the study protocol and statistical analysis plan, will be available
on request.
Supplemental Material
This article contains the following supplemental material online
at http://links.lww.com/CJN/B846.
Supplemental Appendix
Supplemental Figure 1. Cemdisiran phase 2 IgA nephropathy
study design.
Supplemental Figure 2. Comparison of 24-hour UPCR at week 32
in predefined subgroups of patients treated with cemdisiran
or placebo.
Supplemental Table 1. Representativeness of study participants.
Supplemental Table 2. Change from baseline in 24-hour urine
protein to week 32 in patients treated with cemdisiran compared
with placebo (secondary end point).
Supplemental Table 3. Change from baseline in week 32 in eGFR
in patients treated with cemdisiran compared with placebo (ex-
ploratory end point).
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Jensen Durgé, Sean Barbour, Zainab Sheriff, Paula MacLeod,
Jonathan Barratt, Chee Kay Cheung, Haresh Selvaskandan, Justyna
Sklarzewicz, Daniel Cattran, Heather N. Reich, Paul Ling, Arenn
Jauhal, Francois Chantrel, Jimmy Grellier, Camille Alzina, Jin Bor
Chen, Kuan-Hsing Chen, Hsiang-Hao Hsu, Huang-Yu Yang, Kun-
Hua Tu, Montserrat Diaz Encarnacion, Helena Marco Rusi~ nol, Luz
San Miguel Amigo, Beatriz Bardaju de Quixano, Irene Silva Torres,
Mario Espinosa, Isabel López-López, Rocío Regalado, Anders
Fernström, Micael Gylling, Fredrik Uhlin, Fernando Fervenza, Bak
Leong Goh, Fairol H. Ibrahim, Aida Azlin Alias, Tay Li Lian, Billy
Hour, Tyrone Rosales, Veronica Macias, Marwan Kaskas, Antoine
Lanot, Victor Gueutin, Sylvie Brucato, Eric Legrand, Julie
Cabantous, Nadia Martin, Xoana Barros, Cristina Martínez,
Montserrat Capdevila, Irene Rovira, Fariz Safhan Mohamad Nor,
Mohd Kamil Ahmad, Wan Ahmad Syahril Rozli Wan Ali, Tze Jian
Ng, ‘Izzah ‘Atira Hisham, Nur Liyana Kamaronzaman, Nadia
Shahirah Mohamed Asri, Mohamad Haziq Abu Othman, Mohd
Shahril Mohd, Olivier Moranne, Kok Peng Ng, Shok Hoon Ooi,
Joan Torras Ambros, Ana Coloma, Juliana Draibe, Claudia Galofre,
Stephan Troyanov, Guylaine Marcotte, Russell Villanueva, Donnah
Franceska De Leon, Ming-Ju Wu, Shan Lee, Rosnawati Yahya,
Seow Yeing Yee, Wan Hazlina Wan Mohamad, Nurul Zaynah
Nordin, Muhamad Zaimi Abdul Wahab, Zurina Che Rohani, Mohd
Alfaisal Mod Baharuddin, Muhamad Nur Asswad Md Kassim, Siti
Nur Zuhafifah Mohd Zaki, See Cheng Yeo, Ru Sin Lim, Siew Hwa
Soh, Felicia Lee, Hongli Jiao, Rosa Lim, Kai Yan Lin, Philippe Zaoui,
Pierre-Louis Carron, David Tartry, Mathilde Bugnazet, Farida
Imerzoukene, Florence Theo, Séverine Dhion, Meryll Argoud,
Gaëlle Vial, Audrey Lehman, and Thierry Romanet.

AFFILIATIONS

1
Department of Cardiovascular Medicine, University of Leicester, Leicester, United Kingdom
2
Mount Elizabeth Novena Hospital, Singapore, Singapore
3
Renal Medicine, Tan Tock Seng Hospital, Singapore, Singapore
4
Department of Nephrology, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
5
University of British Columbia, Division of Nephrology, Vancouver, British Columbia, Canada
6
Johns Hopkins University School of Medicine, Baltimore, Maryland
7
National Kidney and Transplant Institute, Quezon City, Philippines
8
Department of Internal Medicine, Taichung Veterans General Hospital and Department of Post-Baccalaureate Medicine, College of Medicine,
National Chung Hsing University, Taichung, Taiwan
9
Alnylam Pharmaceuticals, Cambridge, Massachusetts
10
Toronto General Hospital, Toronto, Ontario, Canada