ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 2529

Liver Function Test Levels with Sarilumab Treatment in Phase 3 Trials: Analysis By Baseline Liver Function Test (LFT) Level

John Tesser1, Gregory St. John2, Toshio Kimura2, Stefano Fiore3, Maureen Rischmueller4, José A. Maldonado-Cocco5, Jürgen Braun6 and Jeffrey Kaine7, 1Arizona Arthritis & Rheumatology Associates, Glendale, AZ, 2Regeneron Pharmaceuticals, Inc., Tarrytown, NY, 3Clinical Science, Sanofi Genzyme, Bridgewater, NJ, 4The University of Adelaide, Adelaide, Australia, 5Buenos Aires University School of Medicine, Buenos Aires, Argentina, 6Ruhr-University Bochum, Bochum, Germany, 7Sarasota Arthritis Research Center, Sarasota, FL

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: , , ,

Session Information

Date: Tuesday, October 23, 2018

Title: Rheumatoid Arthritis – Treatments Poster III: Biosimilars and New Compounds

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

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 adalimumab-controlled MONARCH (NCT02332590) and placebo-controlled 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 post-baseline measurement of ALT or AST were categorized by baseline and maximum on-study ALT, AST, total bilirubin, and alkaline phosphatase (AP).

Results:

In MOBILITY (MTX-IR), among patients with normal ALT at baseline (n=1085), maximum on-study 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 on-study 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 on-study 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 (TNF-IR; 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 sarilumab-treated patients.

Conclusion:

LFT elevations with sarilumab, an IL-6R 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 on-treatment LFTs in 52-week MOBILITY study of sarilumab+csDMARDs in patients with RA and inadequate response to MTX (MTX-IR)

 

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 on-treatment 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 on-treatment 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 on-treatment 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 on-treatment 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; apercentage of treatment group; bpercentage of baseline category within treatment group. LLN, lower limit of normal

 

Table 2. Maximum on-treatment LFTs in 24-week 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 on-treatment 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 on-treatment 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 on-treatment 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 on-treatment 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; apercentage of treatment group; bpercentage of baseline category within treatment group. LLN, lower limit of normal


 

Table 3. Maximum on-treatment LFTs in 24-week 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 on-treatment 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
n=171 (94%)a

>ULN

n=8 (4.4%)a

LLN–ULN
n=177 (98%)a

>ULN
n=4 (2.2%)a

LLN–ULN
n=173 (94%)a

>ULN
n=9 (4.9%)a

Maximum on-treatment 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
n=169 (93%)a

>ULN
n=0

LLN–ULN
n=175 (97%)a

>ULN
n=0

LLN–ULN
n=170 (92%)a

>ULN
n=1 (0.5%)a

Maximum on-treatment 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
n=167 (92%)a

>ULN
n=14 (7.7%)a

LLN–ULN
n=158 (87%)a

 >ULN
n=23 (13%)a

LLN–ULN
n=155 (84%)a

>ULN
n=29 (16%)a

Maximum on-treatment 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; apercentage of treatment group; bpercentage of baseline category within treatment group; n/a, not applicable. LLN, lower limit of normal

 

Disclosure: J. Tesser, Sanofi Genzyme/Regeneron, Abbvie, 2, 8,Sanofi Genzyme/Regeneron, 5; G. St. John, Regeneron Pharmaceuticals Inc., 1, 3; T. Kimura, Regeneron Pharmaceuticals Inc., 1, 3; S. Fiore, Sanofi Genzyme, 1, 3; M. Rischmueller, Member of the Australian sarilumab advisory board, 9,Investigator on the TARGET and MOBILITY trials, 9; J. A. Maldonado-Cocco, Pfizer, Merck Sharp Dohme, Sanofi – Aventis, Novartis, Bristol Myers Squibb, Roche, Boehringer Ingelheim, Schering – Plough, Abbott, UCB, Eli Lilly, Gilead, 5, 8; J. Braun, None; J. Kaine, Sanofi Genzyme, Regeneron Pharmaceuticals Inc., 2, 5, 8.

To cite this abstract in AMA style:

Tesser J, St. John G, Kimura T, Fiore S, Rischmueller M, Maldonado-Cocco 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/liver-function-test-levels-with-sarilumab-treatment-in-phase-3-trials-analysis-by-baseline-liver-function-test-lft-level/. Accessed .

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