title: Recombinant human anti-transforming growth factor beta1 antibody therapy in systemic sclerosis: a multicenter, randomized, placebo-controlled phase I/II trial of CAT-192.
abstract: 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.
authors.affiliation: Royal Free Hospital, London, UK. c.denton@medsch.ucl.ac.uk
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Denton
authors.forename: Peter A
authors.initials: PA
authors.lastname: Merkel
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Furst
authors.forename: Dinesh
authors.initials: D
authors.lastname: Khanna
authors.forename: Paul
authors.initials: P
authors.lastname: Emery
authors.forename: Vivien M
authors.initials: VM
authors.lastname: Hsu
authors.forename: Nancy
authors.initials: N
authors.lastname: Silliman
authors.forename: James
authors.initials: J
authors.lastname: Streisand
authors.forename: John
authors.initials: J
authors.lastname: Powell
authors.forename: Anita
authors.initials: A
authors.lastname: Akesson
authors.forename: John
authors.initials: J
authors.lastname: Coppock
authors.forename: Frank van den
authors.initials: Fv
authors.lastname: Hoogen
authors.forename: Ariane
authors.initials: A
authors.lastname: Herrick
authors.forename: Maureen D
authors.initials: MD
authors.lastname: Mayes
authors.forename: Douglas
authors.initials: D
authors.lastname: Veale
authors.forename: Joanna
authors.initials: J
authors.lastname: Haas
authors.forename: Stephen
authors.initials: S
authors.lastname: Ledbetter
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Korn
authors.forename: Carol M
authors.initials: CM
authors.lastname: Black
authors.forename: James R
authors.initials: JR
authors.lastname: Seibold
mesh_terms: 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
chemical_list: 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