Effect of finerenone
on chronic kidney
disease outcomes in
type 2 diabetes
Rajiv Agarwal
on behalf of G.L. Bakris, R. Agarwal, S.D. Anker, B. Pitt,
L.M. Ruilope, P. Rossing, P. Kolkhof, C. Nowack,
P. Schloemer, A. Joseph, G. Filippatos, and the
FIDELIO-DKD international investigator team
23 October 2020
Global burden of kidney failure – diabetes is the leading cause
7600 million – global population
844 million – global prevalence of CKD
3.9 million – patients on KRT
As many might die due to lack of KRT
CKD, chronic kidney disease
Estimates for 2017. Jager KJ, et al. NDT 2019;34:1803
3
FIDELIO-DKD rationale
High residual risk of CKD progression with current therapies
RENAAL3
Composite primary endpoint*
Hemodynamic1,2
(elevated blood pressure
and/or intraglomerular 60
RR=16%; p=0.02
Patients with an event (%)
pressure)
50
Placebo
40 Losartan
30
20
10
Residual risk
0
0 12 24 36 48
Months of study
*Composite of doubling of serum creatinine, ESKD or death
1. Alicic RZ, et al. Clin J Am Soc Nephrol 2017;12:2032; 2. Mora-Fernández C, et al. J Physiol 2014;18:3997;
3. Brenner BM, et al. N Engl J Med 2001;345:861
4
FIDELIO-DKD rationale
High residual risk of CKD progression with current therapies
CREDENCE3
Cardiorenal composite endpoint*
Hemodynamic1,2
(elevated blood pressure
and/or intraglomerular 25 HR=0.70 (95% CI 0.59–0.82); p=0.00001
Patients with an event (%)
pressure)
20 Placebo + ACEi/ARB
Canagliflozin + ACEi/ARB
15
Metabolic1,2
(poor glycemic control) 10
5 Residual risk
Residual risk
0
0 6 12 18 24 30 36 42
Months since randomization
*Composite of kidney failure, doubling of serum creatinine, or renal or CV death
1. Alicic RZ, et al. Clin J Am Soc Nephrol 2017;12:2032; 2. Mora-Fernández C, et al. J Physiol 2014;18:3997;
3. Perkovic V, et al. N Engl J Med 2019;380:2295
5
FIDELIO-DKD rationale
High residual risk of CKD progression with current therapies
Hemodynamic1,2
(elevated blood pressure
and/or intraglomerular
pressure)
Inflammation
and fibrosis1–3
Metabolic1,2
(poor glycemic control)
Not specifically targeted by
existing treatments1,4
1. Alicic RZ, et al. Clin J Am Soc Nephrol 2017;12:2032; 2. Mora-Fernández C, et al. J Physiol 2014;18:3997;
3. Bauersachs J, et al. Hypertension 2015;65:257; 4. Alicic RZ, et al. Adv Chronic Kidney Dis 2018;25:1941
6
FIDELIO-DKD rationale
Finerenone MR
Finerenone is a novel, selective, non-steroidal
MRA that inhibits inflammation and fibrosis and
protects against progressive kidney and CV
dysfunction in preclinical models1
ARTS-DN (patients with CKD and T2D) DNA
– finerenone improved albuminuria
independent of measured changes in BP2
Hypothesis: MR antagonism with finerenone slows CKD progression and
reduces CV morbidity and mortality in patients with advanced CKD and T2D3
MR, mineralocorticoid receptor; MRA, mineralocorticoid receptor antagonist
1. Agarwal R, et al. Eur Heart J 2020. In Press; 2. Bakris GL, et al. JAMA 2015;314:884;
3. Bakris GL, et al. Am J Nephrol 2019;50:333
7
FIDELIO-DKD eligibility criteria
Key inclusion criteria Key exclusion criteria
• Aged ≥18 years with CKD and T2D • Non-diabetic kidney disease, including
• Pretreated with optimized therapy, including an ACEi or clinically relevant renal artery stenosis
ARB at a max tolerated dose for ≥4 weeks • HFrEF with NYHA class II–IV
• Serum potassium ≤4.8 mmol/L • HbA1c >12%
• Diabetic retinopathy for patients with A2 albuminuria • Uncontrolled arterial hypertension*
Albuminuria categories (mg albumin/g creatinine)
A1 A2 A3
Normal to mildly elevated Moderately elevated Severely elevated
0–29 30–299 ≥300–4999
G1 >90
GFR categories
(mL/min/1.73 m2)
G2 60–89
G3a 45–59
G3b 30–44
G4 15–29
G5 <15
*Mean sitting SBP ≥170 mmHg or mean sitting DBP ≥110 mmHg at the run-in visit or mean sitting SBP ≥160 mmHg or mean sitting DBP
≥100 mmHg at the screening visit
8 8
FIDELIO-DKD study design
13,911 patients 5734 patients randomized 2.6 years’ median follow-up
enrolled
Post-treatment
Finerenone 10 or 20 mg od* follow-up
Run-in (4–16 weeks) Screening R
Post-treatment
Placebo follow-up
Hierarchical endpoints
1. Kidney composite 2. CV composite 3. Death from any cause
Time to kidney failure, Time to CV death, Hospitalization for
4. any cause
sustained ≥40% decrease non-fatal MI,
in eGFR from baseline, or non-fatal stroke
or hospitalization 5. Change in UACR
renal death
for HF
6. Second kidney composite
*10 mg if screening eGFR <60 mL/min/1.73 m2; 20 mg if ≥60 mL/min/1.73 m2, uptitration encouraged from month 1 if
serum potassium ≤4.8 mEq/L and eGFR stable. eGFR, estimated glomerular filtration rate; HF, heart failure;
9 9
Patients were randomized from 48 countries worldwide
Europe (n=2358; 41.6%)
North America
(n=944; 16.6%)
Asia (n=1579, 27.8%)
Oceania
Latin America (n=101, 1.8%)
(n=593; 10.5%) Africa
(n=99, 1.7%)
5734 patients randomized – 5674 patients in FAS –
99.7% completed the study
FAS, full analysis set
10
Baseline demographics and medications
Finerenone Placebo
(n=2833) (n=2841)
Mean age, years 65 66
Male, % 69% 71%
Mean duration of T2D, years 16.6 16.6
Mean HbA1c, % 7.7 7.7
Blood pressure, mmHg 138/76 138/76
Mean serum [K+], mmol/L 4.4 4.4
ACEis, % 34 35
ARBs, % 66 65
Glucose-lowering therapies, % 97 98
Insulin and analogs 65 63
GLP-1RAs 7 7
SGLT-2is 4 5
GLP-1RA, glucagon-like peptide-1 receptor agonist; SGLT-2i, sodium-glucose co-transporter-2 inhibitor
11
Baseline kidney labs – balanced between treatment groups
eGFR (mL/min/1.73 m2) UACR (mg/g)
UACR
eGFR ≥60
30–<300
11.6% 12.1%
eGFR <45 eGFR 45–<60
54.9% 33.5%
UACR ≥300
87.5%
Mean eGFR 44 Median UACR ~850
0.4% of patients had a UACR <30 mg/g
12
Albuminuria (UACR) change over time
1,2
(–4.7%) (–3.0%) (–2.0%) (4.1%)
LS mean ratio to baseline
1,0
Placebo
Finerenone
0,8
0,6
(–34.7%) (–41.3%) (–39.9%) (–29.3%)
0,4
0,2
LS mean ratio: 0.69 (0.66–0.71)*
0,0
0 4 8 12 16 20 24 28 32 36
Months since randomization
31% reduction in UACR at month 4 with finerenone vs placebo
Data in parenthesis are mean change from baseline, error bars 95% CIs
*Between baseline and month 4 (prespecified secondary outcome); LS, least-squares
13 13
Blood pressure and blood glucose
Max delta -3.2 at month 4 vs
Change in SBP (mmHg) over time +0.7 with placebo
160
Placebo
Mean SBP
Finerenone
135
110
0 4 8 12 16 20 24 28 32 36 40 44
Change in HbA1c (%) over time
10
Mean HbA1c
9
8
7
6
5
0 4 8 12 16 20 24 28 32 36 40 44
Months since randomization
14 14
Primary endpoint
Kidney failure*, sustained ≥40% decrease in eGFR from baseline, or renal death
40 HR=0.82 (95% CI 0.73–0.93) Placebo (600/2841)
Cumulative incidence (%)
p=0.0014
Finerenone (504/2833)
30
20
10
0
0 6 12 18 24 30 36 42 48
Time to first event (months)
No. at risk
Placebo 2841 2586 1758 792 82
Finerenone 2833 2607 1808 787 83
*ESKD or an eGFR <15 mL/min/1.73 m2
15 15
Components of the primary kidney-specific
composite endpoint
Finerenone Placebo
(n=2833) (n=2841) p-
Endpoint Hazard ratio (95% CI)
value
n (%) n (%)
0.82
Primary composite kidney endpoint 504 (17.8) 600 (21.1) 0.0014
(0.73–0.93)
0.87
Kidney failure 208 (7.3) 235 (8.3) –
(0.72–1.05)
0.86
End-stage kidney disease 119 (4.2) 139 (4.9) –
(0.67–1.10)
Sustained eGFR 0.82
167 (5.9) 199 (7.0) –
<15 mL/min/1.73 m2 (0.67–1.01)
Sustained ≥40% decrease in eGFR 0.81
479 (16.9) 577 (20.3) –
from baseline (0.72–0.92)
Renal death 2 (<0.1) 2 (<0.1) – –
0,50 1,00 2,00
Favors finerenone Favors placebo
n refers to number of patients with event
PY, patient-years
16
Key secondary endpoint
CV death, non-fatal MI, non-fatal stroke, or hospitalization for HF
25
HR=0.86 (95% CI 0.75–0.99)
Cumulative incidence (%)
Placebo (420/2841)
20 p=0.0339 Finerenone (367/2833)
15
10
0
0 6 12 18 24 30 36 42 48
Time to first event (months)
No. at risk
Placebo 2841 2653 1969 951 115
Finerenone 2833 2688 2017 984 111
17
Hierarchical endpoint analysis
Finerenone Placebo
Endpoint (n=2833) (n=2841) Hazard ratio (95% CI) p-value
n (%) n (%)
Primary kidney 0.82
1 504 (17.8) 600 (21.1) 0.0014
composite endpoint (0.73 – 0.93)
Key secondary CV 0.86
2 367 (13.0) 420 (14.8) 0.0339
composite endpoint (0.75 – 0.99)
Death from any 0.90
3 219 (7.7) 244 (8.6) 0.2348
cause (0.75 – 1.07)
Hospitalization from 0.95
4 1263 (44.6) 1321 (46.5) –
any cause (0.88 – 1.02)
0.69
5 Change in UACR* – – –
(0.66 – 0.71)*
Secondary composite 0.76
6 252 (8.9) 326 (11.5) –
kidney endpoint# (0.65 – 0.90)
0,50 1,00 2,00
Favours Favours
finerenone placebo
n refers to number of patients with event
*Ratio of least-squares mean; #Kidney failure, sustained ≥57% decrease in eGFR from baseline, or renal death (with a ≥57% decrease in
eGFR from baseline being equivalent to doubling of serum creatinine)
18
Efficacy summary
NNT for primary and key secondary endpoints over 3 years
Primary Secondary
kidney endpoint CV endpoint
NNT=29 NNT=42
(95% CI 16–166) (95% CI 22–397)
• Modest effects on blood pressure
• Consistent effects on components of primary endpoint
• Consistent effects across key subgroups, including eGFR and UACR at baseline
19
Investigator-reported treatment-emergent adverse events
Finerenone Placebo
Safety outcome, n (%)
(n=2827) (n=2831)
Any AE 2468 (87.3) 2478 (87.5)
AE related to study drug 646 (22.9) 449 (15.9)
AE leading to treatment discontinuation 207 (7.3) 168 (5.9)
Any serious AE 902 (31.9) 971 (34.3)
Serious AE related to study drug 48 (1.7) 34 (1.2)
Serious AE leading to treatment discontinuation 75 (2.7) 78 (2.8)
Most common AEs leading to treatment discontinuation
Hyperkalemia 51 (1.8) 19 (0.7)
Blood potassium increased 13 (0.5) 6 (0.2)
AE, adverse event
20
Change in serum potassium over time
5,4
(0.25) (0.24) (0.21) (0.21) (0.20)
5,2
Mean serum [K+] (mmol/L)
Mean serum [K+] at baseline:
5,0 Finerenone: 4.4±0.5
4,8 Placebo: 4.4±0.5
4,6
4,4
4,2
4,0
3,8 (0.02) (0.04) (0.05) (0.07) (0.07)
3,6
0 4 8 12 16 20 24 28 32 36 40 44
Months since randomization
Maximum mean difference in serum potassium between groups
= 0.23 mmol/L at month 4
Data in parenthesis are mean change from baseline; error bars show standard deviation
21
Investigator-reported treatment-emergent adverse events
related to hyperkalemia
Treatment-emergent AE
Any treatment-emergent AE with clinical consequences Finerenone (n=2827)
treatment-emergent AE (%)
25
Placebo (n=2831)
516
20 (18,3%)
Patients with a
15 333
255 (11,8%)
10 (9,0%)
135
(4,8%) 64
5 25 40
(2,3%) 8 0 0
(0,9%) (1,4%)
(0,3%) (0%) (0%)
0
Any Related to study Leading to Leading to Leading to death
drug permanent hospitalization
discontinuation
Investigator-reported AEs relating to hyperkalemia*
*Using the MedDRA preferred terms ‘hyperkalemia’ and ‘blood potassium increased’
22
Investigator-reported treatment-emergent adverse events
related to acute kidney injury
Treatment-emergent AE
Any treatment-emergent AE with clinical consequences Finerenone (n=2827)
treatment-emergent AE (%)
8
Placebo (n=2831)
Patients with a
6 129 136
(4,6%) (4,8%)
4
53 47
34 (1,9%) (1,7%)
2 (1,2%) 18
5 7 0 1
(0,6%)
(0,2%) (0,2%) (0%) (<0.1%)
0
Any Related to study Leading to Leading to Leading to death
drug permanent hospitalization
discontinuation
Investigator-reported AEs relating to acute kidney injury
’
23
Safety summary
In a patient population with advanced CKD on maximally tolerated dose of
ACEi/ARB, and excepting temporary withdrawal of study drug, K+ management
was at the investigator’s discretion:
• Finerenone was well tolerated
• Overall treatment-emergent adverse events were similar between groups
• Finerenone led to a mean increase in serum [K+] of 0.2 mmol/L across
subpopulations vs placebo
Although hyperkalemia increased, it was manageable; only 2.3% of patients
discontinued finerenone vs 0.9% on placebo
24
Benefit–risk in studies investigating RAS inhibition
in similar patient populations
ALTITUDE1 VA NEPHRON-D2
(CKD + T2D) (CKD + T2D)
Lack of efficacy Lack of efficacy Kidney and CV efficacy
25 25 25
Aliskiren + ACEi/ARB ACEi + ARB (n=724) Finerenone + ACEi/ARB
(n=4272) (n=2827)
Permanent discontinuation
due to hyperkalemia (%)*
20 Placebo + ACEi/ARB 20 Placebo + ARB (n=724) 20 Placebo + ACEi/ARB
(n=4285) (n=2831)
15 15 15
9.9%
10 10 10
4.8% 4.4%
5 2.6% 5 5
2.3%
0.9%
0 0 0
Median 2.7 years Median 2.2 years Median 2.6 years
*Hyperkalemia in VA NEPHRON-D was reported as defined as potassium level >6.0 mEq/L, emergency room visit or admission for hyperkalemia
1. Parving HH, et al. N Engl J Med 2012:367:2204; 2. Fried LF, et al. N Engl J Med 2013;369:1892
25
Benefit–risk in studies investigating RAAS inhibition
in similar patient populations
AMBER1
(CKD)
Efficacy not studied
Kidney and CV efficacy
(Phase II)
40 40
Placebo + spiro + Finerenone + ACEi/ARB
ACEi/ARB (n=148) (n=2827)
Permanent discontinuation
due to hyperkalemia (%)*
Patiromer + spiro + Placebo + ACEi/ARB
30 ACEi/ARB (n=147) 30 (n=2831)
20 23.0% 20
10 6.8% 10
2.3%
0.9%
0 0
12 weeks Median 2.6 years
1. Agarwal R, et al. Lancet 2019:394:1540
26
Overall summary and conclusions
In patients with CKD and T2D treated with optimized RAS therapy,
finerenone was well-tolerated and significantly reduced:
The risk of The risk of CV
CKD progression morbidity and
by 18% mortality by 14%
27 27
Thank you
48 countries, 1024 sites, 13,911* participants
Executive committee
George L. Bakris; Gerasimos Filippatos; Rajiv Agarwal; Stefan D. Anker; Luis M. Ruilope; Bertram Pitt
Independent data monitoring committee
Murray Epstein; Aldo Maggioni; Glenn Chertow; Gerald DiBona; Tim Friede; Jose Lopez-Sendon; Jean Rouleau
Clinical event committee
Rajiv Agarwal; Stefan Anker; Phyllis August; Andrew Coats; Hans Diener; Wolfram Döhner; Barry Greenberg;
Stephan von Haehling; James Januzzi; Alan Jardine; Carlos Kase; Sankar Navaneethan; Lauren Phillips;
Piotr Ponikowski; Pantelis Sarafidis; Titte Srinivas; Turgut Tatlisumak; John Teerlink
National lead investigators
Augusto Vallejos; Richard MacIsaac; Guntram Schernthaner; Pieter Gillard; Maria Eugenia F. Canziani; Theodora Temelkova-Kurktschiev;
Ellen Burgess; Sheldon Tobe; Fernando González; Zhi-Hong Liu; Andrés Ángelo’ Cadena Bonfanti; Carlos Francisco Jaramillo; Martin Prazny;
Peter Rossing; Jorma Strand; Michel Marre; Roland Schmieder; Christoph Wanner; Pantelis Sarafidis; Juliana Chan; László Rosivall;
Joseph Eustace; Ehud Grossman; Yoram Yagil; Giuseppe Remuzzi; Daisuke Koya; Takashi Wada; Magdalena Madero Rovalo; Ron Gansevoort;
Adriaan Kooy; Trine Finnes; Froilan De Leon; Janusz Gumprecht; Fernando Teixeira e Costa; Alexander Dreval; Anantharaman Vathsala;
Aslam Amod; Sin Gon Kim; Byung Wan Lee; Julio Pascual Santos; Bengt-Olov Tengmark; Michel Burnier; Chien-Te Lee; SukitYamwong;
Ramazan Sari; Kieran McCafferty; Borys Mankovsky; Sharon Adler; Linda Fried; Robert Toto; Mark Williams;Tran Quang Khan
The FIDELIO-DKD team would also like to thank all participating
investigators, the centers, the patients and their families
*Number of patients who provided informed consent
28
