Download - L. obici final
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KiactaTM (Eprodisate disodium) for the
Treatment of AA Amyloidosis
Clinical Phase 3 Trial Top Line Results
Dr. Laura Obici
Amyloid Research and Treatment Center Fondazione IRCCS
Policlinico San Matteo
Pavia, Italy
ISA July 06, 2016
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• Rare, life-threatening disease: high morbidity/mortality
• The most serious complication of chronic inflammation
• Amyloid fibrils derived from circulating SAA accumulate
in major organs: predominately the kidneys
• Often delayed diagnosis and most likely underdiagnosed
• No specific treatment currently available
-Current standard of care consists in treating aggressively the
underlying disease
-These treatments are often toxic and not sufficiently efficacious in
many patients
AA Amyloidosis: Disease Overview
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Rheumatoid
Arthritis
21%
Other chronic
inflammatory
arthritides
7%
Bronchiectasias
3%
Castleman's
2% Unknown
21%
Crohn's disease
12%
Cystic Fibrosis
4%
Other
7%
TRAPS
6%
FMF
7%
HIDS
2%
MWS
3% Schnitzler's
1%
Obesity
4%
AA amyloidosis: Pavia experience 2000-2015
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↑ SAA (SAA1) (serum amyloid A precursor protein)
Amyloid A fibril
formation &
deposition
Kidney
Spleen
GI tract
Liver
Damage to:
AA protein + Sulfated glycosaminoglycans (GAGs)
Long-standing inflammatory diseases (RA, FMF, CD)
TNFα / IL-1 / IL-6
AA Amyloidosis:
Kiacta Mechanism of Action
Kiacta blocks AA + GAGs interaction
X
Abnormal processing
of SAA
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Dose-dependent reduction of amyloid
deposits in spleen with Kiacta
Kiacta decreases amyloid burden in
spleen shown by Congo red staining
Control KIACTA (30mg/ml)
• • • •
•
•
AA Amyloidosis Mouse Model:
Preclinical Proof-of-Concept
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6
Eprodisate Dosage
Readjustment needed with changes in renal function so as to
achieve same blood concentrations
Orally administered capsules (400 mg)
Patient Group
Based on creatinine clearance (CrCl)
Dosing Regimen
Dose (mg/day)
CrCl 80 mL/min 1200 mg bid 2400
30 CrCl 80 mL/min 800 mg bid 1600
20 CrCl < 30 mL/min 400 mg bid 800
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7
First Kiacta Phase 2/3 Study Design
0 24mos 52 mos
Placebo (N=94)
KIACTA (N=89)
KIACTA (N=110)
Open label extension Randomized, double-blind
• Primary Efficacy Endpoint was a composite assessment of renal
function deterioration/death defined as:
― 50% reduction in creatinine clearance (CrCl), or
― 100 % increase in serum creatinine (SCr), or
― End-stage renal disease (ESRD)/dialysis, or
― all-cause mortality
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0
5
10
15
20
25
30
35
40
45
50
PlaceboKIACTA
Kiacta reduces renal function decline
by 42% when compared to placebo
HR 0.58 0.41 0.48 0.54 0.95
95% C.I 0.37, 0.93 0.19,0.86 0.28,0.82 0.22,1.37 0.27,3.29
P value 0.025 0.019 0.008 0.20 0.94
Composite
Primary Endpoint Doubling
SCr
50% decrease
CrCI
Dialysis/
ESRD Death
Nu
mb
er
of
Pa
tie
nt
Eve
nts
*
*
*
Primary Composite Endpoint:
Cox Proportional Hazards Analysis
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Primary Composite Endpoint: Time to first Event of
Renal Function Decline or Death
HR=0.58
Wald Chi Square test: p=0.025
Kiacta
Placebo
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Phase 2/3 Open Label Extension Study: Significant
Improvement in Time to First Worse Event and Time to ESRD
Cox Proportional Hazards Regression Model Analysis
Baseline = Month 0 of DB
Eprodisate/ eprodisate
(N = 89)
Placebo/ eprodisate
(N = 94)
HR p-value*
First worse event 39 58 0.59 0.011
Doubling SCr 16 31 0.49 0.023
50% decrease CrCl 30 45 0.58 0.021
Dialysis/ESRD 8 19 0.39 0.026
Death 7 8 0.82 0.70
* From Wald Chi Square Test, adjusted for baseline nephrotic status
41% reduction in risk of disease worsening in eprodisate group (p=0.011)
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International Phase III Study of the Efficacy and Safety of
KiactaTM in Preventing Renal Function Decline in Patients
with AA amyloidosis
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Kiacta Phase 3 Study Design
Placebo (N= 130) + Standard of care
Kiacta (N=131) + Standard of care
Screen 1 Screen 2 Baseline M3 M6 M9 M12 M15………M52
(M -3) (Wk -1) (Wk 0)
• 261 patients enrolled by 57 sites from 30 countries
• Multicenter, randomized, double-blind placebo controlled
• Event-driven trial (study ends when 120 renal events are achieved)
• Patients stratified at baseline based on:
o Proteinuria < 3g/day or ≥ 3g/day; o eGFR < 60 ml/min/1.73m2 or ≥ 60 ml/min/1.73m2
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30 Countries involved in Phase 3 Trial
• Finland Armenia Germany
• France Egypt Bulgaria
• Israel Estonia Czech Republic
• Italy Georgia Ukraine
• Lithuania India
• Netherlands Jordan
• Poland Latvia
• Russia Lebanon
• Spain Mexico
• Tunisia Peru
• Turkey Portugal
• UK Sweden
• USA Belgium
Countries in black were involved in both
Phase 2/3 and Phase 3 trials
Countries in red were involved in Phase 3
trial only
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Key Study Entry Criteria
• Age 18-80 years old
• Positive biopsy (CR and immunohistochemistry) for AA
• Proteinuria ≥ 1g/day on two visits 1 week apart during screening
• CrCl ≥25 ml/min/1.73m2 on two visits 1 week apart during screening
• Absence of any other kidney diseases
• Stables doses of anti-inflammatory / immunomodulator agents for 3
months prior to baseline
• Signed informed consent
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Statistical Analysis Plan
• Composite Primary Efficacy Endpoint (renal function deterioration):
o Persistent increase in serum creatinine ≥ 80% , or o Persistent decrease in creatinine clearance ≥ 40%, or o Progression to ESRD/dialysis
Primary Efficacy Analysis: time to first event (Log Rank test)
• Secondary Efficacy Endpoint
o Slope of CrCl
• Other Key Exploratory Efficacy Endpoints
o Primary composite endpoint including all-cause mortality
o Time to ESRD, time to ≥ 40% decrease in CrCl; ≥ 80% increase in SCr
o Change from baseline in proteinuria
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Reasons for Screen Failures: 201 Patients
Proteinuria < 1g/day
23%
CrCl < 25 ml/min/1.73m2
24%
Negative biopsy
35%
Other
18%
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Patient Disposition
Placebo Kiacta Total
Number enrolled 131 130 261
Number completed 94 91 185 (70.9%)
Early Termination 37 39 76 (29.1%)
Reasons for Early Termination
Death 13 15 28
Voluntary withdrawal 12 10 22
Physician decision 5 7 12
Adverse Event 5 4 9
Lost to follow up 2 2 4
Protocol violation 0 1 1
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Demographics and Baseline characteristics
Placebo
(n=131)
Kiacta
(n= 129)
Age
Sex
Median (Min, Max)
%M / %F
48.0 (19, 79)
51.9 / 48.1
43.0 (18, 78)
55.8 / 44.2
SAA (mg/L)
CRP (mg/L)
Median (Min, Max)
Median (Min, Max)
20.3 (1.0, 747.0)
7.9 (0.1, 175.9)
13.9 (0.8, 989.0)
6.8 (0.2, 120.0)
SCr (mg/dL)
CrCl (ml/min/1.73m2)
Proteinuria (g/24h)
Nephrotic syndrome
Median (Min, Max)
Median (Min, Max)
Median (Min, Max)
% Nephrotic
1.00 (0.2, 5.6)
65.0 (12, 272)
4.2 (0.5, 56.5)
70.2
1.10 (0.2, 4.2)
73.0 (20, 303)
4.7 (0.6, 22.9)
72.9
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Underlying Inflammatory Diseases
50
13
19
24
41
19
23
26
ARTHRITIS CHRONIC INFECTION FMF OTHER
Placebo Kiacta
% P
ati
en
ts
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Concomitant Medications
51,5%
10,9%8,5%
24,2%
7,8%
33,3%
24,5%
18,3%
68,8%
28,2%
0%
10%
20%
30%
40%
50%
60%
70%
80%
Colchic
ine
imm
unosuppressiv
e agents
Corticoste
roid
s
Biolo
gics
meth
otrexate
% o
f P
ati
en
ts
Kiacta
Placebo
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Primary Efficacy Analysis: Time to first Event of
Renal Function Deterioration* (Log Rank test)
P = 0.882
* Deterioration of renal function; ≥ 40% decrease in CrCl; ≥ 80% increase in SCr; or progression to ESRD
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0
10
20
30
40
50
60
70
80
Placebo
KIACTA
Composite Primary Efficacy Endpoints:
Cox Proportional Hazard Ratio Analysis
HR 1.0 1.1 1.0 0.8
95% C.I 0.6-1.8 0.7-1.6 0.7-1.4 0.5-1.5
P value 0.943 0.773 0.870 0.549
Composite
Primary Endpoint
80% increase
SCr 40% decrease
CrCI
Dialysis/
ESRD
Nu
mb
er
of
Pa
tie
nt
Eve
nts
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Secondary Efficacy Endpoint: Slope of
Creatinine Clearance
Placebo
(n = 131)
Kiacta
(n = 130)
P-value
Mean (SD) (ml/min/1.73m2/mo) -1.75 (3.44) -1.88 (4.42)
Median (ml/min/1.73m2/mo) -0.99 -0.77
0.756
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Safety Data
87
49
4 13
85
45
3
15
ALL ADVERSE EVENTS
SERIOUS ADVERSE EVENTS
ADVERSE EVENTS LEADING TO
DISCONTINUATION
DEATHS
Placebo Kiacta
% P
ati
en
ts
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Most Frequent Adverse Events (All-Causalities)
13
17.6
8.4
13
9.4 10.7
17.1
11.6 12.4 12.4
10
6.2
Placebo Kiacta
% P
ati
en
ts
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Comparisons of Key Parameters Between
Phase 2/3 and Phase 3 trials
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Main Differences in Study Design of Phase 2/3 and
Phase 3 Trials
Previous Phase 2/3 Study
• Primary composite endpoint
• 100% increase SCr
• 50% decrease CrCl
• Progression to ESRD
• All-cause mortality
• Inclusion criteria
• Proteinuria ≥ 1g/d or CrCL ≤ 60 ml/min
• CrCl ≥ 20 ml/min
• Fixed duration of study (2 years)
• Statistical Analysis
• Stats power ~ 80% (74 events)
• p <0.01
Current Phase 3 study
• Primary composite endpoint
• Persistent 80% increase SCr
• Persistent 40% decrease CrCl
• Progression to ESRD
• Inclusion criteria
• Proteinuria ≥ 1g/d • CrCl ≥ 25 ml/min
• Event-driven trial (120 primary events)
• Statistical analysis
• Stats power ~ 90% (120 events)
• p < 0.05
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Comparison of Baseline Characteristics
in Phase 2/3 Versus Phase 3 Trial
First Phase 2/3
Trial
(n=183)
Phase 3 Trial
(n= 261)
Age
Sex
Median (Min, Max)
%M / %F
52.0 (21, 77)
42.1 / 57.9
46.0 (18, 79)
53.8 / 46.2
SAA (mg/L)
CRP (mg/L)
Median (Min, Max)
Median (Min, Max)
21.0 (0.8, 424.0)
10.3 (0.2, 110.0)
18.3 (0.8, 989.0)
6.9 (0.1, 175.9)
SCr (mg/dL)
CrCl (ml/min/1.73m2)
Proteinuria (g/24h)
Nephrotic syndrome
Median (Min, Max)
Median (Min, Max)
Median (Min, Max)
% Nephrotic
1.20 (0.3, 4.1)
58.0 (9, 265)
3.1 (0.03, 18.9)
39.9
1.00 (0.2, 5.6)
68.0 (12, 303)
4.5 (0.5, 56.4)
71.5
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Comparison of Underlying Disease and Concomitant
Medication in Phase 2/3 versus Phase 3 trials
Phase 2/3 Trial
(n = 183)
Phase 3 Trial
(n = 261)
Arthritic Conditions 66.7% 45.4%
Chronic Infectious Diseases 14.2% 15.8%
Hereditary Fever 19.7% 21.2%
Other 12.1% 25.4%
Phase 2/3
(n = 183)
Phase 3
(n = 261)
Oral Corticosteroids 70.4% 60.8%
Colchicine 30.2% 30.8%
Biologics 12.0% 24.3%
Methotrexate 18.0% 15.0%
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Conclusion
• Kiacta Phase 3 trial is the largest study ever conducted in AA amyloidosis
and provides invaluable information on the natural course of disease
• Demographics and baseline characteristics were well balanced between
study groups
• Kiacta did not meet the primary efficacy endpoint in slowing renal function
decline in the Phase 3 confirmatory trial
• Kiacta was shown to be safe and well tolerated over 4 years of treatment
• Further analysis of the data are ongoing to better understand topline results
of Phase 3 trial and the difference in study outcome between Phase 2/3 and
phase 3 trials
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Thank You
Patients
Investigators
Study Coordinators