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

Abstract

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-TGF␤1 drug. In this pilot study, CAT-192, in doses up to 10 mg/kg, showed no evidence of efficacy. The utility of

A Thrombospondin-1 Antagonist of Transforming Growth Factor-β Activation Blocks Cardiomyopathy in Rats with Diabetes and Elevated Angiotensin II

“…14,73 Consistent with data from our previous in vitro studies, in the DAAC model the TSP1 antagonist peptide reduced only the excessive, stimulated levels of TGF-␤ activity and had no effects on basal levels of activity as measured in immunoblots for phosphorylated Smad 2. Because TGF-␤ activity is required for tissue homeostasis, 64,65 the ability to selectively target the pathological excess of TGF-␤ activity, without abrogating normal homeostatic levels of activity, represents an important therapeutic advantage for any antifibrotic approach that targets TGF-␤.…”

Dermal Melanocortin Receptor Rebound in Diffuse Systemic Sclerosis after Anti‐TGFβ1 Antibody Therapy

“…Interestingly, Denton et al [7] did not find any improvement in modified Rodnan score after CAT-192 therapy in dSSc of recent onset, nor were there any changes in TGFb mRNA content in skin biopsies taken before and after treatment in this study. We were thorough, though, to take biopsies from the advancing edge of the skin lesion, where TGFb mRNA may be assumed to reach its highest levels and the effects of therapy might be most pronounced.…”

“…A TGFb responsive gene signature may also be found in the skin of dSSc patients with severe disease [6]. These findings prompted the CAT-192 study, which comprised treatment of dSSc with infusions of a recombinant human anti-TGFb1 antibody [7].…”

“…Recently, a multi-centre, randomized, placebo-controlled phase I ⁄ II clinical trial was carried through in the US and Europe, treating recent onset dSSc with infusions of a recombinant human anti-TGFb1antibody (the CAT-192 study) [7]. The aim was to impede vascular and skin lesions, and to prevent ILD.…”

Interactions entre la Fibrilline-1 et le TGF-β

“…Un essai thérapeutique randomisé de phase II a été réalisé chez 43 patients atteints de ScS, qui ont reçu des anticorps anti-TGF-β (CAT-192) ou un placebo. La tolérance a été satisfaisante mais aucune réduction de la fibrose dermique n'a été observée [24]. Cependant, la spécifi-cité de CAT-192 semble discutée et de nouveaux essais sont envisagés avec de nouveaux anticorps monoclonaux plus spécifiques du TGF-β.…”