ObjectivesTo evaluate safety and efficacy of weekly (qw) and every other week (q2w) dosing of sarilumab, a fully human anti-interleukin 6 receptor α (anti-IL-6Rα) monoclonal antibody, for moderate-to-severe rheumatoid arthritis (RA).MethodsIn this dose-ranging study, patients (n=306) with active RA, despite methotrexate, were randomly assigned to placebo or one of five subcutaneous doses/regimens of sarilumab: 100 mg q2w, 150 mg q2w, 100 mg qw, 200 mg q2w, 150 mg qw for 12 weeks, plus methotrexate. The primary end point was ACR20 at Week 12. Secondary endpoints included ACR50, ACR70, Disease Activity Score in 28 joints (C reactive protein). Safety, pharmacokinetics, pharmacodynamics and efficacy in population subgroups were assessed.ResultsThe proportion of patients achieving an ACR20 response compared with placebo was significantly higher for sarilumab 150 mg qw (72.0% vs 46.2%, multiplicity adjusted p=0.0203). Higher ACR20 responses were also attained with 150 mg q2w (67%; unadjusted (nominal) p=0.0363) and 200 mg q2w (65%; unadjusted p=0.0426) versus placebo. Sarilumab ≥150 mg q2w reduced C reactive protein, which did not return to baseline between dosing intervals. Infections were the most common adverse event; none were serious. Changes in laboratory values (neutropenia, transaminases and lipids) were consistent with reports with other IL-6Rα inhibitors.ConclusionsSarilumab improved signs and symptoms of RA over 12 weeks in patients with moderate-to-severe RA with a safety profile similar to reports with other IL-6 inhibitors. Sarilumab 150 mg and sarilumab 200 mg q2w had the most favourable efficacy, safety and dosing convenience and are being further evaluated in Phase III.
Background Sarilumab is the first fully human monoclonal antibody directed against IL-6Rα. Objectives Part A of the MOBILITY phase 2/3 seamless study evaluated the efficacy and safety of 5 dose regimens of subcutaneous sarilumab on top of methotrexate (MTX) versus placebo plus MTX, for the treatment of rheumatoid arthritis (RA). Methods Adults with active, moderate-to-severe RA who had an inadequate response to treatment with MTX were randomized to 6 groups: sarilumab 100 mg every other week (q2w), 150 mg q2w, 100 mg weekly (qw), 200 mg q2w, 150 mg qw, or placebo. All patients were on background MTX. The primary endpoint was the proportion of patients achieving ACR20 response at Week 12. Results Baseline demographic and disease characteristics of the 306 patients enrolled in the study were similar across groups: 79% female; mean age 52 yrs; disease duration 8 yrs; RF+ 79.7%; tender joint count 27; swollen joint count 17; hsCRP 2.8 mg/dL; and HAQ-DI 1.6. ACR20 response at Week 12 was higher in 4 sarilumab dose groups but statistically significantly greater in the 150 mg qw arm only (72.0%, P=0.02) when compared to placebo (46.2%). At week 12, the 2 sarilumab doses (150 and 200 mg q2w) selected for the subsequent phase 3 (MOBILITY part B), showed statistically significant improvement of at least 3 of the seven ACR core components and marginal significance (p value range >0.01 to <0.02) in a fourth compared to the placebo arm. A post hoc analysis of the ACR20 response based on hsCRP value was performed comparing placebo to that of sarilumab 150 and 200 mg q2w. Results indicated that ACR response to Sarilumab was not correlated to changes in hsCRP. The percentage of patients with ≥1 treatment emergent adverse event (AE) ranged from 43% to 72% for the sarilumab groups versus 47% for placebo. The most common treatment emergent AEs reported in the active treatment arms were infections (non-serious) 12-26%, neutropenia 0-20%, and ALT increase 0-6%. Eight patients (3 receiving sarilumab 100 mg q2w, 3 receiving 100 mg qw, and 2 receiving placebo) experienced at least 1 treatment emergent serious AE. One death (stroke/acute respiratory distress syndrome) occurred in a patient treated with sarilumab. Increases in total cholesterol, LDL and HDL were seen with sarilumab, consistent with those previously observed with the approved IL-6 inhibitor. Conclusions In this phase 2 study, sarilumab 150 mg qw, in combination with methotrexate, demonstrated efficacy in patients with active, moderate-to-severe rheumatoid arthritis, who had inadequate response to MTX. Moreover, for the doses that were selected for phase 3 (150 and 200 mg q2w), sarilumab resulted in an improvement in some ACR core components compared to placebo. The types and incidence of adverse events were consistent with those previously reported with IL-6 inhibition. MOBILITY Part B (SARIL-RA-MOBILITY) the phase 3 portion of the seamless study will assess long-term efficacy of sarilumab in rheumatoid arthritis. Clinical trial identifier: NTC01061736 Disclosure ...
BackgroundPreclinical genetic and pharmacological studies suggest a role for Lysophosphatidic acid (LPA) in the three key processes characterizing systemic sclerosis (SSc): fibrosis, microangiopathy and immunoinflammation.ObjectivesWe have assessed SAR100842, a potent orally available selective antagonist of the LPA1 receptor and explored safety, skin biomarkers of LPA pathway, and clinical efficacy in patients with early diffuse cutaneous SSc (dcSSc) in a phase 2a clinical trial.MethodsACT12339, study NCT01651143 sponsored by SANOFI, was an 8-week double-blind, randomized, placebo-controlled study followed by a 16 week open label extension study with SAR100842. 32 patients with dcSSc <36 months since the onset of the first non-Raynaud's SSc manifestation and an mRSS ≥15 were included. Patients with severe organ involvement that was deemed unsafe were excluded. Background stable immunosuppressant therapy was allowed. The primary endpoint was safety. Secondary end-points included effect on potential biomarkers from skin biopsies and blood samples as well as change in mRSS and S-HAQ at week 8 and 24 in the modified intent to treat (ITT) population defined as any patient with a post investigational product evaluation in each part of the study.Results17 patients were randomized to the placebo group and 15 to the SAR100842 group. 30 patients participated in the extension study.The most frequent adverse events reported under SAR100842 during the blinded period were headache, diarrhea and nausea.No statistically significant difference between the 2 groups was observed in skin biopsy and blood biomarkers at week 8. However, a greater reduction of some skin LPA-induced marker mRNA levels (e.g. Wnt2, PAI1 and SFRP4) was observed in the SAR100842 group compared to placebo, consistent with successful target engagement. At week 8 an improvement in mRSS (median improvement= - 4.0 versus -1.0 units) and in HAQ-DI were observed in the SAR100842 group compared to placebo, respectively.The safety profile was good during the extension part. The most frequent adverse events in this part were headache, arthralgia, fatigue and nausea. After 24 weeks of treatment with SAR100842 key skin fibrotic biomarkers (COMP and TSP1) were reduced from baseline. LPA-associated biomarker mRNA levels were improved after 16 weeks of treatment with SAR100842 in the group of patients who initially received placebo. In parallel, there was a clinically meaningful improvement of clinical parameters as indicated in the table below. 78.5% of patients achieved Minimal Clinically Important Difference estimate of mRSS.ConclusionsSAR100842 was well tolerated in patients with dcSSc and resulted in a reduction of skin thickness assessed by mRSS. The clinical efficacy was supported by biological evidence of the LPA target engagement. Altogether these data suggest that SAR100842 may be an effective treatment for dcSSc which needs to be confirmed in a larger controlled trial.Disclosure of InterestY. Allanore Grant/research support from: Actelion, Bayer, Biogen Idec, B...
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