Genovese_Kremer_Mar2017

Phase 2b Studies of ABT-494, a Selective JAK-1 Inhibitor, in
a Patients With Rheumatoid Arthritis

1. Efficacy and Safety of ABT-494, a Selective JAK-1 Inhibitor, in a Phase
IIb Study in Patients With Rheumatoid Arthritis and an Inadequate
Response to Methotrexate
Mark C. Genovese, Josef S. Smolen, Michael E. Weinblatt, Gerd R. Burmester, Sebastian
Meerwein, Heidi S. Camp, Li Wang, Ahmed A. Othman, Nasser Khan, Aileen L. Pangan and
Steven Jungerwirth
Arthritis Rheumatol 2016;68:2857–66
2. A Phase IIb Study of ABT-494, a Selective JAK-1 Inhibitor, in
Patients With Rheumatoid Arthritis and an Inadequate Response to
Anti–Tumor Necrosis Factor Therapy
Joel M. Kremer, Paul Emery, Heidi S. Camp, Alan Friedman, Li Wang, Ahmed A. Othman,
Nasser Khan, Aileen L. Pangan, Steven Jungerwirth and Edward C. Keystone
Arthritis Rheumatol 2016;68:2867–77

Background and Objectives
• ABT-494 is a novel selective JAK-1 inhibitor
– It is under development for the treatment of moderate to severe RA
• Two Phase 2b studies aimed to compare the efficacy and safety of
various doses of ABT-494 against placebo in RA patients receiving a
stable dose of MTX
– One study included patients with an inadequate response to MTX 1
– The other included patients with an inadequate response to or
intolerance of 1 anti-TNF agent 2
1. Genovese MC, et al. Arthritis Rheum 2016;68:2857–66.
2. Kremer JM, et al. Arthritis Rheum 2016;68:2867–77.

Methods – Eligibility Criteria
• Inclusion criteria:
– Age ≥18 years
– Active RA (≥6/66 swollen joints and ≥6/68 tender joints)
– hsCRP above upper limit of normal (5 mg/L) or seropositive for both
anti-CCP and rheumatoid factor
– Study 1: Active RA despite MTX treatment 1
‣ Patients were required to discontinue all other DMARDs for a
pre-specified duration before baseline 1
– Study 2: Active RA despite ≥1 anti-TNF treatment for ≥3 months 2
‣ Patients had discontinued TNF therapy because of intolerance or toxicity
‣ All biologic agents had to be washed out prior to randomisation
hsCRP, high-sensitivity C-reactive peptide.
1. Genovese MC, et al. Arthritis Rheum 2016;68:2857–66. 2. Kremer JM, et al. Arthritis Rheum 2016;68:2867–77.

Methods – Study Design
• These were Phase 2b, randomised, double-blind, placebo-controlled, parallel-group,
multicentre studies
• Eligible patients were randomised 1:1:1:1:1 to receive either placebo BID or
immediate-release oral doses of ABT-494 at 3 mg, 6 mg, 12 mg or 18 mg BID for 12
weeks
– Study 1 included an additional dose of 24 mg once daily
• Patients continued stable-dose MTX (7.5–25 mg/week) and were to take oral folic
acid (or equivalent) from 4 weeks before baseline and throughout the study
• Concurrent treatment was permitted with stable doses of other, non-DMARD
background RA therapy
• Patients who completed the 12-week randomised controlled study completed a
30-day follow-up visit or had the option to enter an open-label extension study
1. Genovese MC, et al. Arthritis Rheum 2016;68:2857–66.
2. Kremer JM, et al. Arthritis Rheum 2016;68:2867–77.

Methods – Endpoints
• The primary efficacy endpoint was the proportion of patients who
achieved an ACR20 response at Week 12
• Secondary endpoints included:
– Proportion achieving ACR50 and ACR70
– Proportion achieving DAS28(CRP) 3.2 or

Results – Baseline Demographics and Disease Activity (Study 1)
Patient characteristic
Placebo
n=50
3 mg BID
n=50
6 mg BID
n=50
ABT-494
12 mg BID
n=50
18 mg BID
n=50
24 mg QD
n=49
Age, mean (SD), years 55 (12) 53 (12) 55 (12) 56 (12) 55 (14) 56 (12)
Female, n (%) 38 (76) 40 (80) 34 (68) 41 (82) 42 (84) 42 (86)
RA duration, mean (SD), years 5.9 (5.3) 3.9 (3.8) 7.0 (5.5) 9.3 (8.6) 7.3 (7.9) 8.3 (7.1)
Previous non-MTX DMARDs, n
(%)
7 (14) 6 (12) 12 (24) 11 (22) 5 (10) 12 (24)
HAQ-DI score, mean (SD) 1.4 (0.7) 1.3 (0.7) 1.6 (0.7) 1.5 (0.6) 1.6 (0.6) 1.5 (0.7)
DAS28(CRP), mean (SD) 5.6 (1.1) 5.5 (1.1) 5.8 (1.0) 5.6 (0.9) 5.7 (0.8) 5.7 (1.0)
CDAI score, mean (SD) 40 (14) 38 (13) 43 (14) 39 (12) 40 (13) 41 (13)
hsCRP >ULN*, n (%) 27 (54) 25 (50) 31 (62) 26 (52) 28 (56) 33 (67)
hsCRP, high-sensitivity C-reactive peptide; ULN, upper limit of normal (ULN=5 mg/L).
Genovese MC, et al. Arthritis Rheum 2016;68:2857–66.

Results – Baseline Demographics and Disease Activity (Study 2)
Patient characteristic
Placebo
n=56
3 mg BID
n=55
6 mg BID
n=55
ABT-494
12 mg BID
n=55
18 mg BID
n=55
Age, mean (SD), years 58 (12) 57 (13) 56 (12) 59 (11) 57 (12)
Female, n (%) 48 (86) 43 (78) 43 (78) 45 (82) 42 (76)
RA duration, mean (SD),
years
Only 1 prior anti-TNF, n
(%)
Prior non-anti-TNF agent,
n (%)
12.1 (9.0) 11.8 (9.4) 12.3 (10.6) 12.2 (10.2) 10.9 (7.7)
42 (76) 39 (71) 38 (70) 38 (72) 38 (69)
9 (16) 10 (18) 14 (26) 14 (26) 7 (13)
HAQ-DI score, mean (SD) 1.6 (0.7) 1.5 (0.7) 1.6 (0.7) 1.6 (0.6) 1.5 (0.6)
DAS28(CRP), mean (SD) 5.8 (0.9) 5.7 (0.9) 5.9 (0.9) 5.7 (0.9) 5.8 (1.0)
CDAI score, mean (SD) 41 (12) 40 (13) 42 (12) 40 (12) 41 (14)
hsCRP >ULN*, n (%) 28 (50) 35 (64) 34 (62) 33 (60) 35 (64)
hsCRP, high-sensitivity C-reactive peptide; ULN, upper limit of normal (ULN=5 mg/L).
Kremer JM, et al. Arthritis Rheum 2016;68:2867–77.

Results – Primary Endpoint
MTX inadequate responders
Placebo
ABT-494
3 mg
ABT-494
6 mg
ABT-494
12 mg
ABT-494
18 mg
ABT-494
24 mg
ACR20 rate (%) 46 62 68* 80* 64 76*
*P

Response rate (%)
Response rate (%)
Results – ACR20, ACR50 and ACR70 response rates at Week 12
90
80
70
60
50
40
30
20
*
***
**
Study 1 (MTX-IR) 1 Study 2 (TNF-IR) 2 Placebo
*
***
**
* *
**
**
* *
90
80
70
60
50
40
30
20
*
**
***
***
*
**
**
**
** **
ABT-494 3 mg BID
ABT-494 6 mg BID
ABT-494 12 mg BID
ABT-494 18 mg BID
ABT-494 24 mg QD
10
10
0
ACR20 ACR50 ACR70
0
ACR20 ACR50 ACR70
*P

Response rate (%)
Response rate (%)
Results – DAS28(CRP) Change From Baseline at Week 12
60
60
Study 1 (MTX-IR) 1 Study 2 (TNF-IR) 2 DAS28(CRP)3.2
50
**
***
**
**
50
**
DAS(CRP)

Response rate (%)
Response rate (%)
Results – CDAI Change From Baseline at Week 12
50
45
40
35
30
25
20
15
10
5
0
Placebo
*
ABT-494
3 mg BID
*
ABT-494
6 mg BID
*
ABT-494
12 mg
BID
**
ABT-494
18 mg
BID
ABT-494
24 mg QD
50
45
40
35
30
25
20
15
10
5
0
Placebo ABT-494 3
mg BID
Study 1 (MTX-IR) 1 Study 2 (TNF-IR) 2 CDAI10
ABT-494 6
mg BID
ABT-494
12 mg BID
ABT-494
18 mg BID
CDAI2.8
*P

Results – Safety Data Through Week 12 (Study 1)
Adverse events, n (%)
Placebo
n=50
3 mg BID
n=50
6 mg BID
n=50
ABT-494
12 mg BID
n=50
18 mg BID
n=50
24 mg QD
n=49
Any AE 13 (26) 20 (40) 23 (46) 29 (58) 25 (50) 17 (35)
Any SAE 0 0 2 (4) 1 (2) 3 (6) 2 (4)
Any AE leading to discontinuation 1 (2) 1 (2) 1 (2) 1 (2) 5 (10) 1 (2)
AEs of special interest:
Infection 7 (14) 10 (20) 7 (14) 12 (24) 11 (22) 9 (18)
Serious infections 0 0 0 1 (2) 0 0
Cardiovascular event 0 0 0 1 (2)† 0 0
Herpes zoster* 0 1 (2) 0 0 0 2 (4)
Hepatic disorder 0 1 (2) 0 0 2 (4) 0
Malignancy 0 0 1 (2)‡ 0 0 0
*Events involved 1 dermatome in each patient;†Lung cancer on posttreatment Day 10 in a 79-year-old man who had smoked for 40 years and had
a family history of lung cancer; the patient died 3 months later; ‡Cerebrovascular accident adjudicated as an ishemic stroke.
Genovese MC, et al. Arthritis Rheum 2016;68:2857–66.

Results – Safety Data Through Week 12 (Study 2)
Adverse events, n (%)
Placebo
n=56
3 mg BID
n=55
6 mg BID
n=55
ABT-494
12 mg BID
n=55
18 mg BID
n=55
Any AE 25 (45) 26 (47) 31 (56) 37 (67) 39 (71)
Any SAE 1 (2) 2 (4) 2 (4) 0 1 (2)
Any AE leading to discontinuation 2 (4) 0 6 (11) 2 (4) 2 (4)
AEs of special interest*
Infection 12 (23) 11 (20) 12 (22) 22 (40) 21 (38)
Serious infections 1 (2) 0 0 0 0
Cardiovascular event 0 0 1 (2)† 0 0
Herpes zoster 2 (4) 1 (2) 0 1 (2) 1 (2)
Hepatic disorder 1 (2) 0 0 0 2 (4)
Malignancy 0 0 1 (2)‡ 0 0
*Reported by the investigator; †Adjudicated as a transient ischemic attack by an externally led cardiovascular adjudication committee;
‡Basal cell and squamous carcinoma.
Kremer JM, et al. Arthritis Rheum 2016;68:2867–77.

Conclusions
• Selective JAK-1 inhibition with ABT-494 was effective in:
– Patients with active RA and an inadequate response to MTX who were
receiving background MTX
– Refractory patients with an inadequate response to or intolerance of 1 anti-
TNF agent
• ABT-494 demonstrated a safety and tolerability profile consistent with other JAK
inhibitors in RA
– With high dosages (12/18 mg BID), the rate of infections was increased (40% in the 12 mg
BID group 2 )
• Larger Phase 3 trials are underway to confirm the selectivity of ABT-494 against JAK-
1 and to determine whether this translates to an improved benefit–risk profile
across a wide spectrum of patients with RA
1. Genovese MC, et al. Arthritis Rheum 2016;68:2857–66.
2. Kremer JM, et al. Arthritis Rheum 2016;68:2867–77.