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

Philip J. Mease; Nathan Wei; Edward J. Fudman; Alan J. Kivitz; Joy Schechtman; Robert G. Trapp; Kathryn F. Hobbs; Maria Greenwald; Antony Hou; Stephen A. Bookbinder; Galen E. Graham; Craig W. Wiesenhutter; Larry Willis; Eric M. Ruderman; Joseph Z. Forstot; Michael J. Maricic; Kathryn H. Dao; Charles H. Pritchard; Darrell N. Fiske; Francis X. Burch; H. Malin Prupas; Pervin Anklesaria; Alison E. Heald

doi:10.3899/jrheum.090817

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

Philip J. Mease, Nathan Wei, Edward J. Fudman, Alan J. Kivitz, Joy Schechtman, Robert G. Trapp, Kathryn F. Hobbs, Maria Greenwald, Antony Hou, Stephen A. Bookbinder, Galen E. Graham, Craig W. Wiesenhutter, Larry Willis, Eric M. Ruderman, Joseph Z. Forstot, Michael J. Maricic, Kathryn H. Dao, Charles H. Pritchard, Darrell N. Fiske, Francis X. BurchH. Malin Prupas, Pervin Anklesaria, Alison E. Heald

Medicine, Rheumatology Division

Research output: Contribution to journal › Article › peer-review

95 Scopus citations

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 × 10¹¹, 1 × 10¹², or 1 × 10¹³ 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). Conclusion. 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. The Journal of Rheumatology

Original language	English (US)
Pages (from-to)	692-703
Number of pages	12
Journal	Journal of Rheumatology
Volume	37
Issue number	4
DOIs	https://doi.org/10.3899/jrheum.090817
State	Published - Apr 2010

Keywords

Biological therapy
Clinical trials
Psoriatic arthritis
Rheumatoid arthritis
Tumor necrosis factor inhibitors

ASJC Scopus subject areas

Immunology and Allergy
Rheumatology
Immunology

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10.3899/jrheum.090817

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Mease, P. J., Wei, N., Fudman, E. J., Kivitz, A. J., Schechtman, J., Trapp, R. G., Hobbs, K. F., Greenwald, M., Hou, A., Bookbinder, S. A., Graham, G. E., Wiesenhutter, C. W., Willis, L., Ruderman, E. M., Forstot, J. Z., Maricic, M. J., Dao, K. H., Pritchard, C. H., Fiske, D. N., ... Heald, A. E. (2010). 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. Journal of Rheumatology, 37(4), 692-703. https://doi.org/10.3899/jrheum.090817

@article{b1bcdbc7931a4b6e8006a8a443e8ec6f,

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 × 1011, 1 × 1012, or 1 × 1013 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). Conclusion. 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. The Journal of Rheumatology",

keywords = "Biological therapy, Clinical trials, Psoriatic arthritis, Rheumatoid arthritis, Tumor necrosis factor inhibitors",

author = "Mease, {Philip J.} and Nathan Wei and Fudman, {Edward J.} and Kivitz, {Alan J.} and Joy Schechtman and Trapp, {Robert G.} and Hobbs, {Kathryn F.} and Maria Greenwald and Antony Hou and Bookbinder, {Stephen A.} and Graham, {Galen E.} and Wiesenhutter, {Craig W.} and Larry Willis and Ruderman, {Eric M.} and Forstot, {Joseph Z.} and Maricic, {Michael J.} and Dao, {Kathryn H.} and Pritchard, {Charles H.} and Fiske, {Darrell N.} and Burch, {Francis X.} and Prupas, {H. Malin} and Pervin Anklesaria and Heald, {Alison E.}",

year = "2010",

month = apr,

doi = "10.3899/jrheum.090817",

language = "English (US)",

volume = "37",

pages = "692--703",

journal = "Journal of Rheumatology",

issn = "0315-162X",

publisher = "Journal of Rheumatology",

number = "4",

}

Mease, PJ, Wei, N, Fudman, EJ, Kivitz, AJ, Schechtman, J, Trapp, RG, Hobbs, KF, Greenwald, M, Hou, A, Bookbinder, SA, Graham, GE, Wiesenhutter, CW, Willis, L, Ruderman, EM, Forstot, JZ, Maricic, MJ, Dao, KH, Pritchard, CH, Fiske, DN, Burch, FX, Prupas, HM, Anklesaria, P & Heald, AE 2010, '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', Journal of Rheumatology, vol. 37, no. 4, pp. 692-703. https://doi.org/10.3899/jrheum.090817

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. / Mease, Philip J.; Wei, Nathan; Fudman, Edward J. et al.
In: Journal of Rheumatology, Vol. 37, No. 4, 04.2010, p. 692-703.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Safety, tolerability, and clinical outcomes after intraarticular injection of a recombinant adeno-associated vector containing a tumor necrosis factor antagonist gene

T2 - Results of a phase 1/2 study

AU - Mease, Philip J.

AU - Wei, Nathan

AU - Fudman, Edward J.

AU - Kivitz, Alan J.

AU - Schechtman, Joy

AU - Trapp, Robert G.

AU - Hobbs, Kathryn F.

AU - Greenwald, Maria

AU - Hou, Antony

AU - Bookbinder, Stephen A.

AU - Graham, Galen E.

AU - Wiesenhutter, Craig W.

AU - Willis, Larry

AU - Ruderman, Eric M.

AU - Forstot, Joseph Z.

AU - Maricic, Michael J.

AU - Dao, Kathryn H.

AU - Pritchard, Charles H.

AU - Fiske, Darrell N.

AU - Burch, Francis X.

AU - Prupas, H. Malin

AU - Anklesaria, Pervin

AU - Heald, Alison E.

PY - 2010/4

Y1 - 2010/4

N2 - 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 × 1011, 1 × 1012, or 1 × 1013 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). Conclusion. 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. The Journal of Rheumatology

AB - 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 × 1011, 1 × 1012, or 1 × 1013 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). Conclusion. 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. The Journal of Rheumatology

KW - Biological therapy

KW - Clinical trials

KW - Psoriatic arthritis

KW - Rheumatoid arthritis

KW - Tumor necrosis factor inhibitors

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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

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