ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: L08

High Baseline Serum IL-6 Identifies a Subgroup of Rheumatoid Arthritis Patients with Rapid Joint Damage and Clinical Progression and Predicts Increased Sarilumab Treatment Response

Anita Boyapati1, Jérôme Msihid2, Sergio Schwartzman3, Ernest Choy4, Mark C. Genovese5, Gerd R. Burmester6, Gordon Lam7, Toshio Kimura1, Jonathan Sadeh8 and Neil M.H. Graham1, 1Regeneron Pharmaceuticals, Inc., Tarrytown, NY, 2Sanofi Chilly-Mazarin, Chilly-Mazarin, NJ, France, 3Hospital for Special Surgery, New York, NY, 4CREATE Center, Cardiff University School of Medicine, Cardiff, Great Britain, 5Division of Immunology & Rheumatology, Stanford University, Stanford, CA, 6Charité-Universitätsmedizin Berlin, Free University and Humboldt University of Berlin, Berlin, Germany, 7Atrium Health, Charlotte, NC, 8Sanofi, Bridgewater, NJ

Meeting: 2018 ACR/ARHP Annual Meeting

Date of first publication: October 4, 2018

Keywords: , , ,

Session Information

Date: Tuesday, October 23, 2018

Title: Late-Breaking Abstract Poster Session

Session Type: ACR Late-breaking Abstract Session

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

Background/Purpose:

Clinical application of biomarkers to predict response to therapy is the next frontier in RA.  Despite the key role of IL-6 in RA, the utility of IL-6 to predict prognosis or treatment response in RA is limited. Post-hoc analyses of MOBIILITY (NCT01061736) and MONARCH (NCT02332590) studies investigated if serum baseline IL-6 level was associated with radiographic and clinical responses to sarilumab versus comparator treatment.

Methods:

Baseline IL-6 levels were measured using a validated assay in 1193 patients (pts) randomized to sarilumab (SC 150 or 200 mg q2w) +MTX or placebo (PBO) +MTX, and 300 randomized to sarilumab 200 mg or adalimumab 40 mg q2w. Efficacy was compared between and within treatment groups according to baseline IL-6 tertile using linear and logistic regression.

Results:

All low tertile pts had normal IL-6 levels (<12.5 pg/mL) and >85% of high tertile pts had IL-6 levels ³3x ULN. At baseline, pts in the high tertile had more joint damage, greater disease activity, and elevated levels of CRP vs the low tertile pts (nominal P<0.05; Tables). In the MOBILITY PBO+MTX group, pts in the high tertile developed more joint damage than pts in the low tertile (mean ± SD mTSS progression 4.67 ± 9.80 vs 1.51 ± 5.25 [Figure]; odds ratio 3.3; 95% CI 1.9, 5.6). Clinical and radiographic efficacy (sarilumab+MTX vs PBO+MTX) in MOBILITY improved with increasing baseline IL-6 tertile (Table 1). In MONARCH, sarilumab efficacy vs adalimumab was greater in the high vs low tertile (Table 2) – ACR20/70 for sarilumab vs adalimumab: 89%/30% vs 52%/4% [high tertile] and 64%/18% vs 58%/18% [low tertile]. Data show that high IL‑6 is better than high CRP at predicting efficacy outcomes. The incidence of treatment emergent adverse events was similar across IL-6 tertiles.

Conclusion:

Across clinical and radiographic endpoints, pts with elevated baseline IL-6 levels had greater response to sarilumab compared with MTX or adalimumab than pts with normal IL-6 levels. Prospective validation is warranted to confirm these data.

Acknowledgements:

Study funding and medical writing support (Matt Lewis, Adelphi) provided by Sanofi and Regeneron Pharmaceuticals, Inc.

Table 1 – MOBILITY (pts with an inadequate response to MTX)

Sarilumab 150 mg q2w/200 mg q2w/PBO q2w (all +MTX), n

High IL-6
 (N=398)

146/121/131

Medium IL-6
 (N=398)

129/147/122

Low IL-6
(N=397)

126/128/143

P value

IL-6 level (pg/mL), median [range]

61.0 [31.2–648.7]

17.3 [9.8–30.7]

5.0 [1.6–9.6]

Baseline disease characteristics, mean (SD)

      CRP (mg/L)

36.4 (30.1)

18.4 (15.5)

10.5 (11.6)

*

      HAQ-DI

1.8 (0.7)

1.6 (0.6)

1.6 (0.6)

*

      DAS28-CRP

6.3 (0.8)

5.9 (0.8)

5.6 (0.8)

*

      mTSS

56.7 (65.7)

49.8 (62.1)

40.8 (56.5)

*

      CDAI

43.0 (12.4)

40.1 (12.3)

38.3 (11.6)

*

Mantel-Haenszel odds ratio (95% CI)$ sarilumab 200 mg q2w +MTX versus PBO q2w + MTX (Week 52)

      mTSS progression

0.3 (0.1, 0.4)

0.6 (0.4, 1.0)

0.7 (0.4, 1.1)

**

      ACR20

4.9 (2.8, 8.3)

3.3 (1.9, 5.7)

2.0 (1.2, 3.2)

**

      ACR50

6.4 (3.5, 11.8)

3.4 (1.9, 6.2)

2.0 (1.2, 3.4)

**

      ACR70

7.3 (3.3, 16.3)

3.5 (1.7, 7.4)

1.9 (1.0, 3.8)

**

      DAS28-CRP <2.6

39.3 (9.4, 163.9)

4.4 (2.2, 8.9)

2.5 (1.4, 4.7)

**

      CDAI ≤2.8

42.4 (4.7, 383.4)

3.9 (1.6, 9.5)

1.8 (0.8, 4.0)

**

HAQ-DI improvement ≥0.3     (Wk 16)

3.1 (1.8, 5.2)

2.2 (1.3, 3.7)

1.1    (0.7, 1.8)

**

Top *Kruskal-Wallis test P<0.05 and bottom **nominal P<0.05 for (high vs low) tertile IL-6-by-treatment interaction (logistic regression with treatment, study randomization stratification factors [prior biological use and region], tertile IL-6 at baseline, and tertile IL-6 at baseline-by-treatment interaction as fixed effects)

$Stratified by study randomization stratification factors

Table 2 – MONARCH (pts with an intolerance or inadequate response to MTX)

Sarilumab/adalimumab, n

High IL-6
(N=100)

46/54

Medium IL-6
(N=100)

47/53

Low IL-6
(N=100)

55/45

P value

IL-6 level (pg/mL), median [range]

64.7 [39.6–692.3]

16.2 [7.2–39.5]

2.4 [1.6–7.1]

Baseline disease characteristics, mean (SD)

      CRP (mg/L)

41.5 (34.1)

15.2 (17.1)

5.6 (9.2)

*

      HAQ-DI

1.8 (0.6)

1.6 (0.6)

1.5 (0.6)

*

      DAS28-CRP

6.5 (0.8)

6.0 (0.7)

5.5 (0.8)

*

      CDAI

46.0 (12.2)

42.9 (11.4)

40.6 (11.7)

*

Mantel-Haenszel odds ratio (95% CI)$ sarilumab versus adalimumab (Week 24)

       ACR20

6.6 (2.3, 18.6)

1.2 (0.5, 3.0)

1.4 (0.6, 3.1)

**

       ACR50

5.5 (2.3, 13.2)

1.5 (0.6, 3.5)

1.6 (0.7, 3.7)

**

       ACR70

10.5 (2.3, 48.4)

1.7 (0.6, 4.6)

1.1 (0.4, 3.2)

**

       DAS28-ESR <2.6

33.9 (3.5, 328.7)

5.6 (1.6, 19.4)

1.5 (0.5, 4.4)

**

       DAS28-ESR <3.2

10.5 (3.5, 31.4)

5.1 (1.8, 14.1)

2.6 (1.0, 6.7)

       DAS28-CRP <2.6

18.4 (3.8, 90.0)

4.0 (1.5, 10.9)

2.0 (0.8, 5.3)

**

       DAS28-CRP <3.2

9.2 (3.4, 24.8)

2.2 (1.0, 5.1)

3.2 (1.3, 7.6)

       CDAI ≤10

3.6 (1.4, 9.0)

1.6 (0.7, 3.7)

3.1 (1.2, 7.7)

       HAQ-DI improvement ≥0.3

4.5 (1.8 , 10.9)

1.4 (0.6 , 3.2)

1.4 (0.6 , 3.2)

Top *Kruskal-Wallis test P<0.05 and bottom **nominal P<0.05 for (high vs low) tertile IL-6-by-treatment interaction (logistic regression with treatment, study randomization stratification factors [region], tertile IL-6 at baseline, and tertile IL-6 at baseline-by-treatment interaction as fixed effects)

$Stratified by study randomization stratification factor

Disclosure: A. Boyapati, Regeneron Pharmaceuticals, Inc, 1, 3; J. Msihid, Sanofi, 1, 3; S. Schwartzman, Abbott/AbbVie, Hospira, Pfizer, Genentech, Xian Janssen Pharmaceuticals, Ltd., Novartis, Crescendo Myriad, Regeneron Pharmaceuticals, Ltd, 5,Abbott/AbbVie, Pfizer, Genentech, UCB Pharmaceuticals, Xian Janssen Pharmaceuticals, Ltd., 8,Crescendo Myriad, 5; E. Choy, Amgen, Bio-Cancer, Chugai Pharma, Ferring Pharmaceuticals, Novimmune, Pfizer, Roche, and UCB, 2,Abbvie, Amgen, AstraZeneca, Biogen, BMS, Boehringer Ingelheim, Celgene, Chelsea Therapeutics, Chugai Pharma, Daiichi Sankyo, Eli Lilly, Ferring Pharmacuetical, GSK, Hospita, ISIS, Jazz Pharmaceuticals, Janssen, MedImmune, Merrimack Pharmaceutical, MSD, Na, 6,Amgen, BMS, Boehringer Ingelheim, Chugai Pharma, Eli Lilly, Hospira, MSD, Novartis, Pfizer, Regeneron, Roche, Sanofi-Aventis, and UCB, 8; M. C. Genovese, Sanofi/Genzyme, Genentech/Roche, RPharm, 2,Sanofi/Genzyme, Genentech/Roche, RPharm, 5; G. R. Burmester, AbbVie, Pfizer, UCB, Roche, 2,AbbVie, Lilly, MSD, Pfizer, Sanofi, Roche, UCB, 5,AbbVie, Lilly, MSD, Pfizer, Sanofi, Roche, UCB, 8; G. Lam, Sanofi Genzyme, Regeneron, Bristol Myers Squibb, Janssen, Abbvie, UCB, 5,Regeneron, Bristol Myers Squibb, Janssen, Abbvie, UCB, 8; T. Kimura, Regeneron Pharmaceuticals Inc., 1, 3; J. Sadeh, Sanofi, 1, 3; N. M. H. Graham, Regeneron Pharmaceuticals, Ltd, 1, 3.

To cite this abstract in AMA style:

Boyapati A, Msihid J, Schwartzman S, Choy E, Genovese MC, Burmester GR, Lam G, Kimura T, Sadeh J, Graham NMH. High Baseline Serum IL-6 Identifies a Subgroup of Rheumatoid Arthritis Patients with Rapid Joint Damage and Clinical Progression and Predicts Increased Sarilumab Treatment Response [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/high-baseline-serum-il-6-identifies-a-subgroup-of-rheumatoid-arthritis-patients-with-rapid-joint-damage-and-clinical-progression-and-predicts-increased-sarilumab-treatment-response/. Accessed .

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