Op0245 preservation of Lung Function Observed in a Phase 3 Randomized Controlled Trial of Tocilizumab for the Treatment of Early SSC

Abstract

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...

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“…The disease course of SSc-ILD is heterogeneous and variable, and different patterns have been observed in different studies, including clinical trials [31,37,47,48]. Disease progression is frequent in patients with https://doi.org/10.1183/16000617.0340-2020…”

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“…In the phase III focuSSced study, the decline in median (95% CI) FVC % pred over 48 weeks was 3.9% (−4.8-−1.6) in the placebo arm, and 0.6% (−2.4-−0.9) in the tocilizumab arm [35,47]. These studies of tocilizumab, which focused on skin-related outcomes in dcSSc but assessed FVC as an exploratory end-point, highlight that FVC decline can occur despite normal lung function at baseline (>80% FVC % pred in both studies), with 3-4% loss of FVC % pred in the placebo arm after 1 year [34,47,48]. In addition, these studies provide some evidence that tocilizumab could play a role in preventing progression of ILD in patients with early dcSSc with inflammatory features.…”

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