Background/Purpose:

Sarilumab (SAR) is a fully human mAb directed against IL-6Rα. In phase 2 MOBILITY Part A (NCT01061736), SAR administered SC plus MTX (methotrexate 10-25 mg/wk) achieved primary endpoint of ACR20 at wk 12. Sensitivity analyses for several pharmacodynamic (PD) parameters, modification of disease activity scores, and safety parameters guided selection of 2 doses for Phase 3 studies. These post hoc analyses evaluated the relationship between SAR doses and change from baseline in serum levels of 3 acute phase reactants (APRs): C reactive protein [hs-CRP], serum amyloid A [SAA] and fibrinogen.

Methods:

Pts were randomized to 6 groups: placebo (PBO), SAR 100, 150, 200 mg every other wk (q2w), and 100, 150 mg every wk (qw). Disease characteristics, including systemic inflammation (hs-CRP, SAA and fibrinogen) were collected at baseline and every 2 wks. ANCOVA models were used to analyze treatment effects on change from baseline at each visit to wk 12.

Results:

Baseline characteristics were similar across all groups (n=306): mean age 52.2±12.3 yrs; 79% women; mean disease duration 7.8±8.1 yrs; RF+ 79.7%; mean hs-CRP 2.8±3.0 mg/dL. CRP results by dose group are shown (Figure). After the first dose, all SAR groups >100 mg q2w had robust and sustained suppression of hs-CRP, maintained throughout the dosing intervals. Similar responses were observed with SAA and fibrinogen and were accompanied by an increase of serum albumin levels. The 150 and 200 mg q2w doses had a response rate at wk 12 comparable to doses of 100 and 150 mg qw for PD parameters and clinical response measures, although the 150 mg q2w dose trended toward more favorable outcomes for some safety parameters. Comparisons of 150 and 200 mg q2w doses show that the 200 mg q2w had a greater and earlier suppression of APRs (at wk 2) but the difference was not significant over time. The most common TEAEs reported in all SAR groups were non-serious infections 12-26%, neutropenia 0-20%, and ALT increase 0-6%. Eight pts (none in the PBO and the 150 and 200 mg q2w groups) experienced at least 1 treatment emergent SAE; of these 6 led to permanent treatment discontinuation. There were no infection-related SAEs in pts with grade 3 or 4 neutropenia and total infection rates were similar to PBO. There was 1 death due to respiratory distress syndrome/cerebrovascular accident in 100 mg q2w group.

Conclusion:

SAR 150 and 200 mg q2w doses resulted in a significant suppression of APRs, evident at wk 2, maintained throughout the dosing intervals, and comparable to suppression achieved with qw dosing. These doses also demonstrated comparable ACR results to qw dosing. In consideration for a less frequent dosing, and potential for better safety profiles, the 150 and 200 mg q2w doses were selected for further Phase 3 studies.

Figure: Change in hs-CRP concentration over time