Recombinant human anti-transforming growth factor beta1 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 beta1 (TGFbeta1), 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 TGFbeta1 and TGFbeta2.


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).


CONCLUSIONS
We report the first evaluation of a systemically administered and repeatedly dosed anti-TGFbeta1 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.
Denton
Christopher P
CP
Royal Free Hospital, London, UK. c.denton@medsch.ucl.ac.uk
Merkel
Peter A
PA
Furst
Daniel E
DE
Khanna
Dinesh
D
Emery
Paul
P
Hsu
Vivien M
VM
Silliman
Nancy
N
Streisand
James
J
Powell
John
J
Akesson
Anita
A
Coppock
John
J
Hoogen
Frank van den
Fv
Herrick
Ariane
A
Mayes
Maureen D
MD
Veale
Douglas
D
Haas
Joanna
J
Ledbetter
Stephen
S
Korn
Joseph H
JH
Black
Carol M
CM
Seibold
James R
JR
D000328:Adult; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006304:Health Status; D006801:Humans; D007166:Immunosuppressive Agents / Q000276:immunology*; D007262:Infusions, Intravenous; D007391:International Cooperation; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins; D045743:Scleroderma, Diffuse / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D012867:Skin / Q000187:drug effects / Q000473:pathology; D011795:Surveys and Questionnaires; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053781:Transforming Growth Factor beta2 / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D015415:Biomarkers; D024042:Collagen Type I; D024061:Collagen Type III; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D011994:Recombinant Proteins; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2