title: Safety, tolerability, and clinical outcomes after intraarticular injection of a recombinant adeno-associated vector containing a tumor necrosis factor antagonist gene: results of a phase 1/2 Study.
abstract: OBJECTIVE
  To assess safety and clinical outcomes in patients with inflammatory arthritis after intraarticular (IA) injection of rAAV2-TNFR:Fc, a recombinant adeno-associated viral vector containing the human tumor necrosis factor (TNF) receptor-immunoglobulin (IgG1) Fc fusion (TNFR:Fc) gene.
  
  
  METHODS
  In this phase 1/2 randomized study, adults with persistent moderate or severe inflammation in a target joint, being treated with or without systemic anti-TNF therapy, received a single IA injection of either rAAV2-TNFR:Fc (1 x 10(11), 1 x 10(12), or 1 x 10(13) DNase-resistant particles/ml joint volume) or placebo, followed by open-label rAAV2-TNFR:Fc 12-30 weeks later, depending on when the target joint met predetermined criteria for reinjection.
  
  
  RESULTS
  127 subjects received the first injection of blinded study drug; 95 subjects received open-label rAAV2-TNFR:Fc. Administration site reactions, consisting of transient mild to moderate increases in tenderness and swelling of the injected joint, occurred after 23/191 (12%) rAAV2-TNFR:Fc injections and were dose-dependent. Rates of other adverse events were not dose-dependent. Notable serious adverse events (SAE) included culture-negative septic arthritis in a subject receiving leflunomide and fatal disseminated histoplasmosis considered unrelated to rAAV2-TNFR:Fc in a subject receiving adalimumab. In the phase 2 portion of the study, a 30% decrease in target joint global visual analog scale was observed in 21/50 (42%) rAAV2-TNFR:Fc subjects and 3/16 (19%) placebo subjects 12 weeks after first injection (p = 0.14).
  
  
  CONCLUSIONS
  IA rAAV2-TNFR:Fc resulted in administration site reactions after 12% of injections. A fatal SAE, disseminated histoplasmosis, was considered not related to study agent. Patient-reported outcome measures of clinical response showed greater improvement in treated patients than placebo patients.
authors.affiliation: Seattle Rheumatology Associates, Swedish Medical Center, Seattle, Wahington 98104, USA. pmease@nwlink.com
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Mease
authors.forename: Nathan
authors.initials: N
authors.lastname: Wei
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Fudman
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Kivitz
authors.forename: Joy
authors.initials: J
authors.lastname: Schechtman
authors.forename: Robert G
authors.initials: RG
authors.lastname: Trapp
authors.forename: Kathryn F
authors.initials: KF
authors.lastname: Hobbs
authors.forename: Maria
authors.initials: M
authors.lastname: Greenwald
authors.forename: Antony
authors.initials: A
authors.lastname: Hou
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Bookbinder
authors.forename: Galen E
authors.initials: GE
authors.lastname: Graham
authors.forename: Craig W
authors.initials: CW
authors.lastname: Wiesenhutter
authors.forename: Larry
authors.initials: L
authors.lastname: Willis
authors.forename: Eric M
authors.initials: EM
authors.lastname: Ruderman
authors.forename: Joseph Z
authors.initials: JZ
authors.lastname: Forstot
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Maricic
authors.forename: Kathryn H
authors.initials: KH
authors.lastname: Dao
authors.forename: Charles H
authors.initials: CH
authors.lastname: Pritchard
authors.forename: Darrell N
authors.initials: DN
authors.lastname: Fiske
authors.forename: Francis X
authors.initials: FX
authors.lastname: Burch
authors.forename: H Malin
authors.initials: HM
authors.lastname: Prupas
authors.forename: Pervin
authors.initials: P
authors.lastname: Anklesaria
authors.forename: Alison E
authors.initials: AE
authors.lastname: Heald
mesh_terms: D000256:Adenoviridae; D000328:Adult; D018501:Antirheumatic Agents / Q000009:adverse effects / Q000276:immunology; D001168:Arthritis / Q000276:immunology / Q000628:therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects*; D005822:Genetic Vectors; D006801:Humans; D007111:Immunity, Cellular; D007074:Immunoglobulin G / Q000009:adverse effects* / Q000235:genetics / Q000276:immunology; D007270:Injections, Intra-Articular; D008297:Male; D018579:Patient Selection; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics* / Q000276:immunology / Q000627:therapeutic use; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000235:genetics*
chemical_list: D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha