Recombinant human anti–transforming growth factor β1 antibody therapy in systemic sclerosis: A multicenter, randomized, placebo‐controlled phase I/II trial of CAT‐192

Objective To evaluate CAT‐192, a recombinant human antibody that neutralizes transforming growth factor β1 (TGFβ1), in the treatment of early‐stage diffuse cutaneous systemic sclerosis (dcSSc). Methods Patients with SSc duration of <18 months were randomly assigned to the placebo group or to 1 of 3 CAT‐192 treatment groups: 10 mg/kg, 5 mg/kg, 0.5 mg/kg. Infusions were given on day 0 and weeks 6, 12, and 18. The primary objective of this study was to evaluate the safety, tolerability, and pharmacokinetics of CAT‐192. Secondary outcomes included the modified Rodnan skin thickness score (MRSS), the Scleroderma Health Assessment Questionnaire, assessment of organ‐based disease, serum levels of soluble interleukin‐2 receptor, collagen propeptides (N propeptide of type I [PINP] and type III collagen), and tissue levels of messenger RNA for procollagens I and III and for TGFβ1 and TGFβ2. Results Forty‐five patients were enrolled. There was significant morbidity and mortality, including 1 death in the group receiving 0.5 mg/kg of CAT‐192 and 3 deaths in the group receiving 5 mg/kg of CAT‐192. There were more adverse events and more serious adverse events in patients receiving CAT‐192 than in those receiving placebo, although these events were not more frequent in the high‐dose treatment group. The MRSS improved in all groups during the study, but there was no evidence of a treatment effect for CAT‐192. Improvement in the MRSS correlated with the disease duration (r = −0.54, P = 0.0008). Changes in the PINP level from baseline correlated with changes in the MRSS (r = 0.37, P = 0.027). Conclusion We report the first evaluation of a systemically administered and repeatedly dosed anti‐TGFβ1 drug. In this pilot study, CAT‐192, in doses up to 10 mg/kg, showed no evidence of efficacy. The utility of clinical and biochemical outcome measures and the feasibility of multicenter trials of early dcSSc were confirmed.