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BackgroundThe anti–IL6 receptor-α antibody tocilizumab (TCZ) demonstrated numerical improvement in modified Rodnan skin score (mRSS) and clinically relevant preservation of lung function (LF) (assessed by forced vital capacity [FVC]) in systemic sclerosis (SSc) patients (pts) in a ph 2 trial.1 ObjectivesReport the efficacy and safety (sft) of TCZ vs placebo (PBO) in SSc pts from the double-blind period of ph 3 trial (NCT02453256).MethodsSSc pts were randomly assigned 1:1 to weekly subcutaneous TCZ 162 mg or PBO for 48 wks. Primary endpoint was mean difference (diff) in change (Δ) from baseline (BL) to wk 48 in mRSS for TCZ vs PBO. Key secondary endpoints were ΔBL%-predicted FVC (ppFVC) and time to Tx failure (time from first study treatment (Tx) to first occurrence of death, decline in FVC >10%, increase in mRSS >20% and mRSS ≥5, or occurrence of predefined SSc-related Cx). Chest high-resolution computed tomography (HRCT) and ACR Combined Response in SSc (CRISS) were exploratory endpoints.ResultsOf 106 PBO- and 104 TCZ-treated pts, 81% were women and 31% had previous or concurrent interstitial lung disease based on history. BL mean values were age 48 yrs, SSc duration 23 mts, mRSS 20.4, ppFVC 82.1%, and ppDLCO 75.6%. Mean BL computer-assisted quantitative lung fibrosis of the most affected lobe (QLF-LM) was 4.7% for the PBO group and 5.5% for the TCZ group. At wk 48, the primary endpoint was not significant (ΔBL mRSS: PBO, −4.4; TCZ, −6.1; adjusted least squares mean diff, −1.7 [95% CI: −3.8, 0.3]; p=0.098) (Fig 1A). All p values for other endpoints were nominal. The cumulative distribution of wk 48 ΔBL ppFVC favored TCZ over PBO (median [IQR]: PBO, −3.9 [−7.2, 0.6] vs TCZ, −0.6 [−5.3, 3.9]; van Elteren nominal p=0.0015). The diff in mean ΔBL FVC at wk 48 between Tx groups was 167 mL (95% CI: 83, 250), favoring TCZ (Fig 1B). At wk 48, 5 (5.4%) TCZ-treated pts experienced ≥10% absolute decline in ppFVC compared with 15 (16.5%) for PBO. The HR (95% CI) for time to Tx failure was 0.6 (0.4, 1.1), numerically favoring TCZ (Cox proportional hazards model; p=0.082). ACR CRISS scores favored TCZ over PBO at wk 48: median (IQR), 0.89 (0.09-1.00) vs 0.25 (0.00-0.99) (p=0.023). HRCT showed less progression of lung fibrosis for TCZ than for PBO, which supports the FVC results. Sft results were consistent with Cx of SSc and the established TCZ sft profile; SAEs were reported by 17% of PBO pts and 13% of TCZ pts; serious infections were reported by 7% and 2% of pts, respectively.ConclusionThe primary mRSS endpoint was not met; however, TCZ Tx resulted in clinically relevant differences in FVC with preservation of LFS and improvement in fibrosis, measured by HRCT, in SSc pts.Disclosure of Interests: Dinesh Khanna Shareholder of: Eicos Sciences, Inc, Grant/research support from: Bayer, BMS, Pfizer, Horizon, Consultant for: Actelion Acceleron, Arena, Bayer, BI, BMS, CSL Behring, Corbus, Cytori, GSK, Genentech/Roche, Galapagos, Employee of: Elcos Sciences, Inc, Celia J. F. Lin Shareholder of: Genentech, Employee of: Genentech, Jona...

BackgroundProgressive Interstitial lung disease (ILD) occurs in ∼ 40% of scleroderma (SSc) patients and is the leading cause of death. Oral CYC for 1 year in SSc-ILD led to modest but significant improvements in lung function and dyspnea vs. placebo (Tashkin, NEJM, 2006) but the benefits were lost over the ensuing year and drug therapy was not extended due to the known toxicity profile of CYC. (Tashkin AJRCCM 2007). Preliminary data from uncontrolled clinical studies suggest that MMF may be an effective and safer immunosuppressive therapy than CYC for SSc-ILD.ObjectivesA randomized controlled trial was performed to determine the efficacy, safety and tolerability of mycophenolate mofetil (MMF) administered for two years compared with CYC administered for one year followed by matching placebo for SSc-ILD.Methods142 patients with pulmonary function and high-resolution computed tomography (HRCT) defined SSc-ILD were randomized at 14 centers to receive MMF or CYC. The primary endpoint, change in forced vital capacity (FVC%>predicted) over 24 months, was assessed using a joint longitudinal model (Elashoff, Statist Med 2006).Results126 patients (63 MMF; 63 CYC) had ≥3 months of outcome data and were included in the primary analysis. A greater number of patients on CYC than on MMF prematurely withdrew from (32 vs 20) and failed treatment (2 vs 0), and the time to stopping treatment was significantly shorter in the CYC arm (p=0.019). At 24-months, the adjusted FVC%>predicted had improved by 2.17 in the MMF arm (95% CI, 0.53–3.84; p<0.01) and 2.86 in the CYC arm (95% confidence interval 1.19–4.58; p<0.001) with no significant between-treatment difference (p=0.24). Significant within- (but not between-) treatment improvements in skin score, dyspnea and whole-lung HRCT scores were also observed. Leukopenia and thrombocytopenia occurred more often with CYC (p<0.05). Sixteen deaths occurred (11 CYC; 5 MMF) with most due to underlying disease.ConclusionsIn this first RCT comparing MMF with CYC in SSc-ILD, both agents appeared to have comparable efficacy but MMF was better tolerated with significantly fewer premature withdrawals from treatment and fewer adverse events. These findings support the increasingly common clinical practice of prescribing MMF for this disease.AcknowledgementFunded by the National Heart, Lung, and Blood Institute, National Institutes of Health; number NCT00883129.Disclosure of InterestNone declared

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