l. obici final

1 CONFIDENTIAL - DO NOT DISTRIBUTE.

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


• 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


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


↑ 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


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


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


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


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


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


10

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)


International Phase III Study of the Efficacy and Safety of

KiactaTM in Preventing Renal Function Decline in Patients

with AA amyloidosis


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


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


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


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


Reasons for Screen Failures: 201 Patients

Proteinuria < 1g/day

23%

CrCl < 25 ml/min/1.73m2

24%

Negative biopsy

35%

Other

18%


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


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


Underlying Inflammatory Diseases

50

13

19

24

41

19

23

26

ARTHRITIS CHRONIC INFECTION FMF OTHER

Placebo Kiacta

% P

ati

en

ts


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


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


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


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


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


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


Comparisons of Key Parameters Between

Phase 2/3 and Phase 3 trials


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


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


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%


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


Thank You

Patients

Investigators

Study Coordinators

l. obici final

Investor Relations