Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose:
Sarilumab (SAR) is a fully human monoclonal antibody directed against the alpha subunit of the IL-6 receptor (IL-6Rα) which is currently being evaluated for treatment of rheumatoid arthritis (RA). Patients with active RA have increased CV risk despite lower levels of total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) as well as high density lipoprotein cholesterol (HDL-C) associated with active inflammation. The current work explores further the acute phase relationship of cholesterol levels in relation to measures of inflammation in RA. In particular we evaluated the changes in cholesterol levels following SAR treatment as well as their relationship to decreases in inflammation using data from a 12-wk phase 2 study (MOBILITY Part A [NCT01061736]) of SAR + methotrexate in patients with RA.
Methods:
Patients with RA (n=306) were randomized to one of the following 6 treatment groups: Placebo (PBO), SAR 100, 150, 200 mg every other week (q2w) or 100, 150 mg weekly (qw). Changes from baseline to wk 12 in TC, LDL-C, and HDL-C were assessed in the intent-to-treat (ITT) population (n= 306 patients). These changes, and changes in C-reactive protein (CRP) and serum amyloid A (SAA) levels, were assessed according to tertiles of baseline CRP and SAA levels in the 2 SAR dose groups whose dose regimens were subsequently chosen for study in phase 3 trials (150 mg and 200 mg q2w).
Results:
At wk 12, changes in TC and LDL-C but not HDL-C were statistically significantly greater in the SAR group compared with PBO (TABLE). Patients with the highest baseline levels of inflammation as assessed by the top tertiles of CRP and SAA, showed the largest decreases in inflammation and the largest increases in TC with SAR treatment. Similar trends were observed for LDL-C (TABLE).
Conclusion:
Treatment with sarilumab at either 150 mg or 200 mg every other week in the phase 2 study MOBILITY Part A was associated with increases in TC and LDL-C compared to placebo. These increases in TC and LDL-C observed with sarilumab were associated with both the baseline burden of inflammation assessed by SAA and CRP, as well as the degree of suppression of inflammation by sarilumab. Further investigation of additional CV biomarkers which are less sensitive to the acute phase response and adequately assess CV risk in the setting of high levels of systemic inflammation from active RA may be warranted. The effect of sarilumab on markers of inflammation and lipid parameters will be further evaluated in the Phase 3 program.
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Mean SAA, hsCRP, TC, LDL-C, and HDL-C changes from baseline to 12 weeks grouped by tertiles of baseline SAA and CRP, ITT population, MOBILITY Part A, placebo vs. pooled SAR 150mg and 200 mg q2weeks |
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Mean Change from Baseline to 12 weeks in Biomarker |
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Pooled SAR: Tertile of Baseline SAA (mg/L) |
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Placebo (n=52) |
Pooled SAR (n=103) |
≤12.7 (n=29) |
>12.7 – ≤45.9 (n=32) |
>45.9 (n=29) |
P-trend |
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hsCRP (mg/L) |
-2.5 |
-24.2* |
-5.1 |
-15.6 |
-27.9 |
<0.0001 |
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SAA (mg/L) |
-0.7 |
-59.1* |
6.8 |
-18.5 |
-99.1 |
<0.0001 |
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TC (mmol/L) |
0.07 |
0.61* |
0.31 |
0.53 |
0.82 |
0.0679 |
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LDL-C (mmol/L) |
0.06 |
0.42* |
0.19 |
0.43 |
0.57 |
0.0489 |
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HDL-C (mmol/L) |
0.06 |
0.10 |
0.09 |
0.03 |
0.14 |
0.2175 |
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Pooled SAR: Tertile of Baseline CRP (mg/L) |
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Placebo (n=52) |
Pooled SAR (n=103) |
≤14.2 (n=33) |
>14.2 – ≤27.5 (n=34) |
>27.5 (n=33) |
P-trend |
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|
hsCRP (mg/L) |
-2.5 |
-24.2* |
-3.3 |
-16.6 |
-54.0 |
<0.0001 |
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SAA (mg/L) |
-0.7 |
-59.1* |
-8.3 |
-34.8 |
-142.3 |
<0.0001 |
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TC (mmol/L) |
0.07 |
0.61* |
0.36 |
0.61 |
0.84 |
0.0247 |
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LDL-C (mmol/L) |
0.06 |
0.42* |
0.23 |
0.52 |
0.49 |
0.0338 |
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HDL-C (mmol/L) |
0.06 |
0.10 |
0.04 |
0.08 |
0.17 |
0.4505 |
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P-trend is value for nonparametric signed-rank test across the SAR tertiles; * P value ≤0.05 vs. placebo |
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Disclosure:
C. Charles-Schoeman,
Pfizer Inc,
2,
Bristol-Myers Squibb,
2,
Pfizer Inc,
5,
Regeneron,
5,
Pfizer Inc,
8;
S. P. Weinstein,
Regeneron,
3,
Regeneron,
1;
J. van Adelsberg,
Regeneron,
3,
Regeneron,
1;
T. Momtahen,
Sanofi-Aventis Pharmaceutical,
3,
Sanofi-Aventis Pharmaceutical,
1;
R. Wu,
Regeneron,
3,
Regeneron,
1;
N. Graham,
Regeneron,
3,
Regeneron,
1;
S. Fiore,
Sanofi-Aventis Pharmaceutical,
3.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/sarilumab-a-subcutaneously-administered-fully-human-monoclonal-antibody-inhibitor-of-the-il-6-receptor-alpha-relationship-between-inflammation-suppression-and-changes-in-cholesterol-levels/