Treatment of Rheumatoid Arthritis with a MEK Inhibitor:

Results of a 12-Week, Randomized, Placebo-Controlled

Phase 2 Study in Patients with Active Rheumatoid Arthritis
on a Background of Methotrexate
J Kay, R Morales, L Bellatin, J Brzezicki, P Sirly, A Neitzel, A James, SG Miller,
W Maksymowych, J Yates, S Rojas-Caro, MH Weisman
Disclosures

J. Kay, W. Maksymowych & M. Weisman:

Consultants for Array Biopharma, Inc.

A. Neitzel, A. James, S.G. Miller, J. Yates & S. Rojas-Caro:

Employees & Shareholders of Array Biopharma, Inc.

R. Morales, L. Bellatin, J. Brzezicki & P. Sirly:

None Declared
MEK/ERK Signaling Pathway in Inflammation

MEK (MAPK/ERK kinase)

is a potential target in inflammation:
MEK is a key kinase involved in
mediating and propagating the
effects of pro-inflammatory cytokines:
TNF, IL-1 and IL-6.

Protein therapeutics targeted against

TNF, IL-1 and IL-6 are approved for
treatment of RA.

MEK inhibitors have demonstrated

efficacy in animal models of
rheumatoid arthritis.

MEK inhibitors block osteoclast

differentiation and function in vitro.
ARRY-162

Potent small molecule inhibitor of MEK1/2

IC50 12 nM in enzymatic assays
IC50 5 nM in cellular assays

Highly selective compared to other kinase inhibitors

Unique binding site; ARRY-162 does not compete with ATP binding
No inhibition >30% of other than MEK1 at 1 M in a panel of 220 other kinases

Oral efficacy in acute and sub-chronic animal models of joint inflammation

Carageenan-induced paw edema
Collagen-induced arthritis & adjuvant-induced arthritis

Pharmacokinetics, pharmacodynamics, and safety profile established in

Phase I clinical studies
Single-ascending dose and 14-day multiple ascending dose in healthy volunteers
29-day study in RA patients on a stable MTX dose
ARRY-162-201
Study Design

12-week, Phase 2, randomized, double-blind, placebo-controlled

multicenter study
Study Aims: Investigate the safety, pharmacokinetics, and efficacy of
ARRY-162, administered orally daily in patients with active RA
incompletely responsive to methotrexate
Study Population:
201 patients randomized (1:1:1:1)
Four treatment arms
ARRY-162 10 mg BID
ARRY-162 20 mg BID
ARRY-162 40 mg QD
Placebo
Primary Endpoint: ACR20 response at week 12
ARRY-162-201
Study Design
Key Secondary Endpoints
Efficacy
ACR20/50/70 response at Baseline & Weeks 1, 2, 4, 8, 12 & 16
Components of ACR score at Baseline & Weeks 1, 2, 4, 8, 12 & 16
DAS28-4[CRP] at Baseline & Weeks 1, 2, 4, 8, 12 &16
SF-36 Health Questionnaire (v. 2) at Baseline & Weeks 4, 8, 12 & 16
Overall incidence & time to withdrawal due to lack of efficacy

Safety
Incidence and severity of AEs
Change from baseline in physical examination, clinical chemistries, vital
signs, 12-lead ECG parameters

Pharmacokinetics
Plasma concentrations of ARRY-162 and a metabolite
ARRY-162-201
Clinical Sites

Poland (6 sites)
Hungary (7 sites)
Romania (4 sites)

USA (1 site)

Peru (4 sites)
Brazil (7 sites)

Argentina (6 sites)
Randomized
Europe &
100
North America
South America 101
ARRY-162-201
Key Eligibility Criteria

18 years of age
RA diagnosed by ACR 1987 Revised Criteria
Incompletely responsive to MTX:
6 tender joints (28-joint count)
6 swollen joints (28-joint count)
CRP 10 mg/L
Stable methotrexate dose (10-25 mg weekly) for 6 weeks prior to
screening
No prior biological agents to treat RA

4-week washout period, if on a DMARD in addition to MTX

Could continue on stable background therapy for RA
NSAIDs, opioid analgesics, acetaminophen, aspirin, antimalarials
prednisone 10 mg/day (or equivalent)
ARRY-162-201
Patient Disposition
475
Patients Screened Placebo

10 mg BID
201
Patients Randomized 40 mg QD

20 mg BID

51 Patients 50 Patients 50 Patients 50 Patients ITT Population (n = 201)

Lost to follow-up = 1
Withdrew consent = 1
Low baseline CRP = 1

49 Patients 49 Patients 50 Patients 50 Patients Safety Population (n = 198)

Withdrew consent = 1 Withdrew consent = 1

Efficacy Evaluable
49 Patients 48 Patients 49 Patients 50 Patients Population (n = 196)

Discontinued, n = 7
Discontinued, n = 13
Discontinued, n = 3 AE/SAE = 3 Discontinued, n = 11
AE/SAE = 10
Death = 1 Consent withdrawal = 2 AE/SAE = 8
Consent withdrawal = 2
Consent withdrawal = 2 Lost to followup = 1 Consent withdrawal = 3
Lost to followup = 1
Other = 1

Completed 12 wks treatment

46 Patients 41 Patients 36 Patients 39 Patients (n = 162)
ARRY-162-201
Baseline Demographic Characteristics

Factor Placebo 10 mg BID 40 mg QD 20 mg BID

Female (%) 84 84 86 88
Caucasian (%) 73 76 74 64
Mean age (yr) 52 52 55 51
Mean weight (kg) 74 68 72 67
Mean duration of RA (months) 89.6 93.4 88.6 95.7
RF+ / anti-CCP+ (%) 78 / 86 88 / 90 84 / 90 92 / 90
Never smoked nicotine (%) 75 78 72 72
Mean MTX dose (mg/week) 14.4 13.2 14.5 14.0
Mean duration of MTX (months) 16.3 21.8 18.6 16.1
Mean HAQ 1.6 1.5 1.5 1.5
Mean screening CRP (mg/L) 32 33 31 31
Mean baseline CRP (mg/L) 19 18 24 24
ARRY-162-201
Primary Efficacy Endpoint: ACR20 at 12 Weeks
80
p = 0.459*

ACR20 Response (%) 58 60

60 54
45

40

20

n=51 n=50 n=50 n=50

0
o

D
ID

ID
eb

Q
B

B
ac

g
g

g
m
m

m
Pl

40
10

20

ACR20 at 12 weeks using last observation carried forward (LOCF), based on the intention-to treat (ITT) population
*Global Chi-square test
ARRY-162-201
12-wk response rates using LOCF based on EE population

Europe / North America South America

Week12 ACR Response Rates Week12 ACR Response Rates

Europe/NA, EE, LOCF South America, EE, LOCF
80 Placebo 80 p=0.936 Placebo
10 mg BID 10 mg BID
p=0.351 68.2
64.0
40 mg QD 60.9
59.3
40 mg QD

% Responders
% Responders

58.3
60 53.8 20 mg BID 60 20 mg BID
47.8 p=0.224
39.1
40 34.6
p=0.426 40
31.8
29.2
26.1 p=0.388
19.2 p=0.657 18.5 18.2
20 20 16.0
11.5 12.5 13.0
7.7 7.4
3.8 4.3 4.0

0 0

20

50

70
20

50

70

R
R

C
C

A
A

A
ARRY-162-201
12-wk DAS28-4[CRP] using LOCF based on EE population
Week 12 DAS28-4[CRP] Change
EE, LOCF
0.0 Placebo
Change in DAS28-4[CRP]

10 mg BID
40 mg QD
20 mg BID
(from Baseline)

-0.5

-1.0

-1.5 * ** ***

-2.0

a
s

ic
n

/N

p-value vs. placebo:

io

er
pe
eg

* p = 0.043
ro

A
R

** p = 0.049
Eu

S
ll
A

*** p = 0.080
 ARRY-162-201
12-wk EULAR Response using LOCF based on EE population

Europe / North America South America

Week 12 EULAR Response Week 12 EULAR Response

Europe/NA, EE, LOCF South America, EE, LOCF
80 Placebo 80 Placebo
10 mg BID 10 mg BID
65 40 mg QD 40 mg QD

EULAR Response
EULAR Response

20 mg BID 20 mg BID
60 60 57 55 56

% Achieving
% Achieving

50 52
48 46 46

40 40
33 32 33
30
23 21 22 22 23 22 22
20 20 15
12 12
4
0 0
e

d
e
d
e

e
at

at
on

on

oo
oo
er

er
N

G
G
od

od
M

M
ARRY-162-201
Safety Population

198 patients who received study drug

21 patients discontinued the study due to an AE:

Placebo: 0/49 ( 0%)
10 mg BID: 3/49 ( 6%)
40 mg QD: 10/50 (20%)
20 mg BID: 8/50 (16%)
P < 0.001

Mean number of days of exposure to study drug:

Placebo: 81.4 days
10 mg BID: 78.8 days
40 mg QD: 68.4 days
20 mg BID: 73.0 days
P = 0.026
ARRY-162-201
Most Commonly Reported Treatment-Emergent AEs
By Treatment Group
MedDRA Preferred Placebo 10 mg BID 40 mg QD 20 mg BID
Term N=49 N=49 N=50 N=50
Rash* 4% 20% 30% 44%

Diarrhea 10% 6% 30% 24%

Nausea 0 0 12% 4%

Peripheral Edema 2% 2% 6% 6%

Abnormal Liver 6% 2% 6% 8%
Function Tests**
Urinary Tract 8% 8% 4% 10%
Infection
Bronchitis 4% 4% 2% 8%

*includes events of rash, rash pustular, rash erytematous, rash papular, folliculitis, acne, dermatitis acneiform, eczema, prurigo, rosacea,
urticaria, and erythema
** includes events of alanine aminotransferase increased, aspartate aminotransferase increased, gama-glutamyltransferase increased,
hepatic enzyme increased, liver function test abnormal, and transaminases increased
ARRY-162-201
Severity of Commonly Reported Treatment-Emergent AEs

All ARRY-162 Dose Levels, by Severity (N=149)

MedDRA Preferred
Grade 1 Grade 2 Grade 3
Term
Rash* 18% 12% 1%

Diarrhea 16% 3% 1%

Nausea 4% 1% 0

Peripheral Edema 7% 0 0
Abnormal Liver
5% 0 0
Function Tests**
Urinary Tract
5% 2% <1%
Infection
Bronchitis 1% 3% 0

*includes events of rash, rash pustular, rash erytematous, rash papular, folliculitis, acne, dermatitis acneiform, eczema, prurigo, rosacea,
urticaria, and erythema
** includes events of alanine aminotransferase increased, aspartate aminotransferase increased, gama-glutamyltransferase increased,
hepatic enzyme increased, liver function test abnormal, and transaminases increased
ARRY-162-201
Study Discontinuations Due to AEs by Region

Total
Placebo 10 mg BID 40 mg QD 20 mg BID
Region Treated
N=49 N=49 N=50 N=50
N=149
E. Europe/
0 4% 8% 9% 7%
N. America
South
0 9% 31% 22% 21%
America
ARRY-162-201
Summary

In this study, ARRY-162 administered over 12 weeks was not

effective in treating the signs and symptoms of active RA in
patients with an incomplete response to methotrexate.
High placebo response rate in South America vs. Eastern Europe /
North America may have limited the ability to detect a significant
difference in efficacy between placebo and study drug
In the Eastern European / North American region, but not in South
America, modest trends toward efficacy vs. placebo, based upon:
ACR20 response at Week 12
Change in DAS28-4[CRP] from Baseline
Good EULAR response at Week 12
Most common AEs on study drug were mild to moderate
skin-related disorders & diarrhea
No SAEs related to study drug
 Backup Slide

20
ARRY-162-201:
Mean CRP Over Time

CRP over Time

All Regions, EE, LOCF
Placebo
4 10 mg BID
40 mg QD
CRP (mg/dL)

3 20 mg BID

BL 4 8 12 FU
Week

21