Session Information
Date: Tuesday, October 23, 2018
Session Title: Rheumatoid Arthritis – Treatments Poster III: Biosimilars and New Compounds
Session Type: ACR Poster Session C
Session Time: 9:00AM11:00AM
Background/Purpose:
Sarilumab showed efficacy in RA and superiority to placebo and adalimumab in Phase 3 trials. This post hoc analysis investigated LFT levels in three sarilumab Phase 3 trials.
Methods:
The adalimumabcontrolled MONARCH (NCT02332590) and placebocontrolled TARGET (NCT01709578) and MOBILITY (NCT01061736) studies allowed alanine (ALT) or aspartate aminotransferase (AST) levels ≤1.5x upper limit of normal (ULN) at entry. Patients who received ≥1 dose of sarilumab and had ≥1 postbaseline measurement of ALT or AST were categorized by baseline and maximum onstudy ALT, AST, total bilirubin, and alkaline phosphatase (AP).
Results:
In MOBILITY (MTXIR), among patients with normal ALT at baseline (n=1085), maximum onstudy ALT >3x ULN was seen in 8.0% (n=29) and 7.8% (n=28) of patients in sarilumab 150 and 200 mg + MTX groups, respectively, versus 2.2% (n=8) with placebo + MTX (Table 1). Among patients with ALT >ULN at baseline (n=106), maximum onstudy ALT >3x ULN was seen in 23% (n=9) and 16% (n=6) in sarilumab 150 and 200 mg + MTX groups, respectively, versus 3.6% (n=1) with placebo + MTX. In the monotherapy MONARCH study, the proportion of patients with maximum onstudy ALT >3x ULN was 2.4% (n=4) in patients with normal baseline ALT and 15% (n=2) in patients with baseline ALT >ULN in the sarilumab group, and 1.7% (n=3) and 20% (n=2), respectively, in the adalimumab group (Table 2). ALT elevations in TARGET (TNFIR; Table 3) were less frequent compared with MOBILITY. There were no cases of Hy’s Law attributable to sarilumab treatment. Laboratory investigations (including LFT elevations) led to treatment discontinuation in 0.2–0.6% of placebo and 0.5–2.8% of sarilumabtreated patients.
Conclusion:
LFT elevations with sarilumab, an IL6R blocker recently approved for the treatment of RA, were more likely in combination with csDMARDs than with monotherapy, and more likely in patients with baseline elevations. Incidence of ALT >3x ULN was similar between monotherapy sarilumab and adalimumab. Importantly, LFT elevations rarely necessitated treatment discontinuation
Acknowledgements
Study funding and medical writing support (Matt Lewis, Adelphi Communications) provided by Sanofi and Regeneron Pharmaceuticals, Inc.
Table 1. Maximum ontreatment LFTs in 52week MOBILITY study of sarilumab+csDMARDs in patients with RA and inadequate response to MTX (MTXIR) 


Placebo (N=397) 
Sarilumab 150 mg (N=401) 
Sarilumab 200 mg (N=396) 


Baseline 
Baseline 
Baseline 

ALT 
LLN–ULN 
>ULN 
LLN–ULN 
>ULN 
LLN–ULN 
>ULN 

n=367 (92%)^{a} 
n=28 (7.1%)^{a} 
n=361 (90%)^{a} 
n=40 (10%)^{a} 
n=357 (90%)^{a} 
n=38 (9.6%)^{a} 
Maximum ontreatment value, n (%)^{b} 





LLN–ULN 
251 (68) 
3 (11) 
177 (49) 
4 (10) 
147 (41) 
4 (11) 
>ULN–3x ULN 
108 (29) 
24 (86) 
155 (43) 
27 (68) 
182 (51) 
28 (74) 
>3x ULN–5x ULN 
7 (1.9) 
1 (3.6) 
19 (5.3) 
6 (15) 
20 (5.6) 
4 (11) 
>5x ULN 
1 (0.3) 
– 
10 (2.8) 
3 (7.5) 
8 (2.2) 
2 (5.3) 

Baseline 
Baseline 
Baseline 

AST 
LLN–ULN 
>ULN 
LLN–ULN 
>ULN 
LLN–ULN 
>ULN 

n=381 (96%)^{a} 
n=14 (3.5%)^{a} 
n=374 (93%)^{a} 
n=26 (6.5%)^{a} 
n=374 (94%)^{a} 
n=20 (5.1%)^{a} 
Maximum ontreatment value, n (%)^{b} 





LLN–ULN 
307 (81) 
4 (29) 
216 (58) 
4 (15) 
209 (56) 
8 (40) 
>ULN–3x ULN 
71 (19) 
10 (71) 
145 (39) 
18 (69) 
157 (42) 
10 (50) 
>3x ULN–5x ULN 
3 (0.8) 
– 
7 (1.9) 
3 (12) 
6 (1.6) 
1 (5.0) 
>5x ULN 
– 
– 
6 (1.6) 
1 (3.8) 
2 (0.5) 
1 (5.0) 

Baseline 
Baseline 
Baseline 

Total bilirubin 
LLN–ULN 
>ULN 
LLN–ULN 
>ULN 
LLN–ULN 
>ULN 

n=370 (93%)^{a} 
n=0 
n=370 (92%)^{a} 
n=2 (0.5%)^{a} 
n=370 (93%)^{a} 
n=1 (0.3%)^{a} 
Maximum ontreatment value, n (%)^{b} 





LLN–ULN 
361 (98) 
– 
342 (92) 
– 
335 (91) 
– 
>ULN–1.5x ULN 
9 (2.4) 
– 
17 (4.6) 
– 
23 (6.2) 
1 (100) 
>1.5x ULN–2x ULN 
– 
– 
8 (2.2) 
2 (100) 
9 (2.4) 
– 
>2x ULN 
– 
– 
3 (0.8) 
– 
3 (0.8) 
– 

Baseline 
Baseline 
Baseline 

AP 
LLN–ULN 
>ULN 
LLN–ULN 
>ULN 
LLN–ULN 
>ULN 

n=359 (90%)^{a} 
n=38 (9.6%)^{a} 
n=366 (91%)^{a} 
n=34 (8.5%)^{a} 
n=350 (88%)^{a} 
n=45 (11%)^{a} 
Maximum ontreatment value, n (%)^{b} 





<LLN 
– 
– 
– 
– 
1 (0.3) 
– 
LLN–ULN 
321 (89) 
– 
338 (92) 
12 (35) 
326 (93) 
21 (47) 
>ULN–1.5x ULN 
36 (10) 
29 (76) 
22 (6.0) 
14 (41) 
19 (5.4) 
19 (42) 
>1.5x ULN 
2 (0.6) 
9 (24) 
6 (1.6) 
8 (24) 
4 (1.1) 
5 (11) 
Patients with baseline value <LLN (all LFTs) or missing (total bilirubin or AP) are not shown; ^{a}percentage of treatment group; ^{b}percentage of baseline category within treatment group. LLN, lower limit of normal 
Table 2. Maximum ontreatment LFTs in 24week MONARCH study of sarilumab monotherapy in patients with active RA 


Adalimumab 40 mg q2w (N=184) 
Sarilumab 200 mg q2w (N=184) 


Baseline 
Baseline 

ALT 
LLN–ULN 
>ULN 
LLN–ULN 
>ULN 

n=174 (95%)^{a} 
n=10 (5.4%)^{a} 
n=169 (92%)^{a} 
n=13 (7.1%)^{a} 
Maximum ontreatment value, n (%)^{b} 



LLN–ULN 
137 (79) 
2 (20) 
112 (66) 
2 (15) 
>ULN–3x ULN 
33 (19) 
6 (60) 
53 (31) 
9 (69) 
>3x ULN–5x ULN 
3 (1.7) 
– 
3 (1.8) 
2 (15) 
>5x ULN 
– 
2 (20) 
1 (0.6) 
– 
Missing 
1 (0.6) 
– 
– 
– 

Baseline 
Baseline 

AST 
LLN–ULN 
>ULN 
LLN–ULN 
>ULN 

n=176 (96%)^{a} 
n=8 (4.3%)^{a} 
n=175 (95%)^{a} 
n=7 (3.8%)^{a} 
Maximum ontreatment value, n (%)^{b} 



LLN–ULN 
153 (87) 
3 (38) 
144 (82) 
1 (14) 
>ULN–3x ULN 
19 (11) 
4 (50) 
29 (17) 
6 (86) 
>3x ULN–5x ULN 
3 (1.7) 
– 
2 (1.1) 
– 
>5x ULN 
– 
1 (13) 
– 
– 
Missing 
1 (0.6) 
– 
– 
– 

Baseline 
Baseline 

Total bilirubin 
LLN–ULN 
>ULN 
LLN–ULN 
>ULN 

n=170 (92%)^{a} 
n=1 (0.5)^{a} 
n=164 (89%)^{a} 
n=1 (0.5%)^{a} 
Maximum ontreatment value, n (%)^{b} 



LLN–ULN 
165 (97) 
– 
150 (91) 
1 (100) 
>ULN–1.5x ULN 
4 (2.4) 
– 
7 (4.3) 
– 
>1.5x ULN–2x ULN 
– 
1 (100) 
5 (3.0) 
– 
>2x ULN 
– 
– 
2 (1.2) 
– 
Missing 
1 (0.6) 
– 
– 
– 

Baseline 
Baseline 

AP 
LLN–ULN 
>ULN 
LLN–ULN 
>ULN 

n=168 (91%)^{a} 
n=15 (8.2%)^{a} 
n=170 (92%)^{a} 
n=14 (7.6%)^{a} 
Maximum ontreatment value, n (%)^{b} 



<LLN 
1 (0.6) 
– 
1 (0.6) 
– 
LLN–ULN 
149 (89) 
3 (20) 
158 (93) 
7 (50) 
>ULN–1.5x ULN 
14 (8.3) 
9 (60) 
9 (5.3) 
7 (50) 
>1.5x ULN 
3 (1.8) 
3 (20) 
2 (1.2) 
– 
Missing 
1 (0.6) 
– 
– 
– 
Patients with baseline value <LLN (all LFTs) or missing (total bilirubin or AP) are not shown; ^{a}percentage of treatment group; ^{b}percentage of baseline category within treatment group. LLN, lower limit of normal 
Table 3. Maximum ontreatment LFTs in 24week TARGET study of sarilumab+csDMARDs in patients with RA and inadequate response or intolerance to >1 TNF inhibitor 


Placebo (N=181) 
Sarilumab 150 mg (N=181) 
Sarilumab 200 mg (N=184) 


Baseline 
Baseline 
Baseline 

ALT 
LLN–ULN 
>ULN 
LLN–ULN 
>ULN 
LLN–ULN 
>ULN 

n=164 (91%)^{a} 
n=17 (9.4%)^{a} 
n=163 (90%)^{a} 
n=18 (10%)^{a} 
n=176 (96%)^{a} 
n=7 (3.8%)^{a} 
Maximum ontreatment value, n (%)^{b} 





LLN–ULN 
129 (79) 
4 (24) 
98 (60) 
2 (11) 
92 (52) 
1 (14) 
>ULN–3x ULN 
34 (21) 
12 (71) 
61 (37) 
15 (83) 
75 (43) 
5 (71) 
>3x ULN–5x ULN 
1 (0.6) 
1 (5.9) 
3 (1.8) 
1 (5.6) 
6 (3.4) 
1 (14) 
>5x ULN 
– 
– 
– 
– 
1 (0.6) 
– 
Missing 
– 
– 
1 (0.6) 
– 
2 (1.1) 
– 

Baseline 
Baseline 
Baseline 

AST 
LLN–ULN 
>ULN n=8 (4.4%)^{a} 
LLN–ULN 
>ULN 
LLN–ULN 
>ULN 
Maximum ontreatment value, n (%)^{b} 





LLN–ULN 
147 (86) 
2 (25) 
132 (75) 
1 (25) 
125 (72) 
1 (11) 
>ULN–3x ULN 
24 (14) 
6 (75) 
42 (24) 
3 (75) 
39 (23) 
7 (78) 
>3x ULN–5x ULN 
– 
– 
2 (1.1) 
– 
6 (3.5) 
1 (11) 
>5x ULN 
– 
– 
– 
– 
1 (0.6) 
– 
Missing 
– 
– 
1 (0.6) 
– 
2 (1.2) 
– 

Baseline 
Baseline 
Baseline 

Total bilirubin 
LLN–ULN 
>ULN 
LLN–ULN 
>ULN 
LLN–ULN 
>ULN 
Maximum ontreatment value, n (%)^{b} 





LLN–ULN 
164 (97) 
– 
163 (93) 
– 
150 (88) 
– 
>ULN–1.5x ULN 
4 (2.4) 
– 
9 (5.1) 
– 
13 (7.6) 
– 
>1.5x ULN–2x ULN 
– 
– 
2 (1.1) 
– 
4 (2.4) 
– 
>2x ULN 
1 (0.6) 
– 
– 
– 
2 (1.2) 
– 
Missing 
– 
n/a 
1 (0.6) 
n/a 
1 (0.6) 
1 (100) 

Baseline 
Baseline 
Baseline 

AP 
LLN–ULN 
>ULN 
LLN–ULN 
>ULN 
LLN–ULN 
>ULN 
Maximum ontreatment value, n (%)^{b} 





LLN–ULN 
146 (87) 
– 
149 (94) 
9 (39) 
141 (91) 
12 (41) 
>ULN–1.5x ULN 
18 (11) 
12 (86) 
6 (3.8) 
11 (48) 
11 (7.1) 
12 (41) 
>1.5x ULN 
3 (1.8) 
2 (14) 
2 (1.3) 
3 (13) 
1 (0.6) 
5 (17) 
Missing 
– 
– 
1 (0.6) 
– 
2 (1.3) 
– 
Patients with baseline value <LLN (all LFTs) or missing (total bilirubin or AP) are not shown; ^{a}percentage of treatment group; ^{b}percentage of baseline category within treatment group; n/a, not applicable. LLN, lower limit of normal 
To cite this abstract in AMA style:
Tesser J, St. John G, Kimura T, Fiore S, Rischmueller M, MaldonadoCocco JA, Braun J, Kaine J. Liver Function Test Levels with Sarilumab Treatment in Phase 3 Trials: Analysis By Baseline Liver Function Test (LFT) Level [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/liverfunctiontestlevelswithsarilumabtreatmentinphase3trialsanalysisbybaselineliverfunctiontestlftlevel/. Accessed February 3, 2023.« Back to 2018 ACR/ARHP Annual Meeting
ACR Meeting Abstracts  https://acrabstracts.org/abstract/liverfunctiontestlevelswithsarilumabtreatmentinphase3trialsanalysisbybaselineliverfunctiontestlftlevel/