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.
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.
Mease
Philip J
PJ
Seattle Rheumatology Associates, Swedish Medical Center, Seattle, Wahington 98104, USA. pmease@nwlink.com
Wei
Nathan
N
Fudman
Edward J
EJ
Kivitz
Alan J
AJ
Schechtman
Joy
J
Trapp
Robert G
RG
Hobbs
Kathryn F
KF
Greenwald
Maria
M
Hou
Antony
A
Bookbinder
Stephen A
SA
Graham
Galen E
GE
Wiesenhutter
Craig W
CW
Willis
Larry
L
Ruderman
Eric M
EM
Forstot
Joseph Z
JZ
Maricic
Michael J
MJ
Dao
Kathryn H
KH
Pritchard
Charles H
CH
Fiske
Darrell N
DN
Burch
Francis X
FX
Prupas
H Malin
HM
Anklesaria
Pervin
P
Heald
Alison E
AE
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*
D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha