Table 3 Efficacy (therapeutic or prophylactic) in animal models of rheumatoid arthritis (RA) of drugs suspended from phase II or III clinical development as treatments for RA

Mechanism	Example	Rat AIA		Rat CIA		Mouse CIA		References
Mechanism	Example	Prophylactic	Therapeutic	Prophylactic	Therapeutic	Prophylactic	Therapeutic	References
Phase III:
TACE inhibitor	DPC 333 (BMS-561392)				+	+		Lorenz et al107
Anti-cytokine, anti-T cell	Esonarimod	++	++					Noguchi et al108
NSAID	Amiprilose	++		++	++			Kieval et al109
Increase T suppressor cells	Nuclomedone			+	−			Komoriya et al110
PGE synthesis inhibitor	FK 3311	+		+				Harris et al, Tsuji et al101 111
MMP inhibitor	Cipemastat (Trocade)	−	–	−				Ishikawa et al112

Phase II
Th2 induction, NFκB inhibition	IL11		+		+		+	Albert et al, Walmsley et al113 114
Decrease IL1 release	TOK-8801	+		+		++	++
VLA-4 antagonist	ZD-7349					+
Dual COX/LT inhibitor	Tepoxalin		+					Argentieri et al74
Complement inhibitor (humanised anti-C5) monoclonal antibody)	Eculizumab (5G1.1)						+	Linton and Morgan, Wang et al24 115
Antibody to IL12p40	IL12 mAb (ABT 874)						+
O₂radical scavenger	Superoxide dismutase	++	++					Shingu et al116
P38 MAP kinase inhibitor	Doramapimod (BIRB 796)						+	Nabozny et al117
P38 MAP kinase inhibitor	TAK 715	+						Miwatashi et al118
Bisphosphonate, IL1 antagonist	TRK 530	+				+		Tanahashi et al, Takaoka et al119^–121
ICE inhibitor	Pralnacasan (VX740)						+	Linton, Ku et al122 123
IL4 (B cell stimulatory factor 1)	IL4					+	+	Cottard et al, Kim et al124 125
Oral TNFα inhibitor	AGIX-4207			+				Sundell et al126
MCP-1 inhibitor	Bindarit		+					Guglielmotti et al127
Immunomodulator	SM 8849	++	++			+		Nagai et al128
IFNβ	Rebif						+	van Holten et al129
Targets α (v) β 3	RGD-4C__D(KLAKLAK)₂					+		Gerlag et al130

+, Efficacy; −, no effect. Where there is a ++ sign covering prophylactic and therapeutic efficacy, efficacy was demonstrated but it was not possible to determine whether it was prophylactic or therapeutic efficacy from the information available.
AIA, adjuvant-induced arthritis; CIA, collagen-induced arthritis; COX, cyclo-oxygenase; ICE, interleukin 1β converting enzyme; IFN, interferon; IL, interleukin; LT, leukotriene; mAb, monoclonal antibody; MAP, mitogen activated protein; MCP, monocyte chemoattractant protein-1; MMP, matrix metalloproteinase; NFκB, nuclear factor κB; NO, nitric oxide; NSAID, non-steroidal anti-inflammatory drug; PGE₂, prostaglandin E₂; RA, rheumatoid arthritis; TACE, TNFα converting enzyme; Th, T helper; TNF, tumour necrosis factor; VLA-4, very late antigen-4.