Table 3.

Summary of TLR4 antagonists used in clinical trials

TLR4 antagonist	Condition/disease	Mechanism of action	Clinical trial design and aim	Trial status and outcome	Reference/clinical trial number
Eritoran (E5564)	Sepsis/severe sepsis/septic shock	Lipid A mimic, binds to MD2	Phase 2, a safety and efficacy study of intravenous E5564 in patients with severe sepsis	Completed. Eritoran appeared well tolerated and showed a lower mortality rate (105 mg dose) in patients with severe sepsis and high predicted risk of mortality.	NCT00046072
			Phase 3, a controlled comparison of eritoran tetrasodium and placebo in patients with severe sepsis	Completed. Patients with severe sepsis did not have reduced 28-day mortality when administered with eritoran, compared with placebo.	NCT00334828
Resatorvid (TAK-242)	Severe sepsis	Binds covalently to Cys747 of TLR4-TIR domain and blocks TLR4/TIRAP and TLR4/TRAM interactions	Phase 3, a pivotal, multicentre, multinational, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of TAK-242 in adults with severe sepsis	Completed. TAK-242 did not suppress cytokine levels in patients with sepsis. TAK-242 was well tolerated but patients developed mild increases in serum methemoglobin levels.	NCT00143611
			Phase 3, randomized, double-blind, placebo-controlled study of the efficacy and safety of TAK-242 vs. placebo in subjects with sepsis-induced cardiovascular and respiratory failure	Terminated. Business decision; no safety or efficacy concerns.	NCT00633477
NI-0101	Healthy volunteers	Monoclonal antibody blocking TLR4 signalling	Phase 1, randomized double-blind study to determine the safety, tolerability and distribution and elimination of a novel therapeutic drug (NI-0101) when administered to healthy volunteers.	Completed. NI-0101 showed good tolerability, favorable safety and PK profile, and durable anti-inflammatory effect in healthy volunteers.	NCT01808469
	Rheumatoid arthritis		Phase 2, randomized, placebo-controlled, double-blind study to explore the effect of a new antibody to treat patients with rheumatoid arthritis.	Completed. Results unavailable.	NCT03241108

E5564 eritoran, MD2 myeloid differentiation factor 2, TAK-242 resatorvid, TLR4 toll-like receptor 4, TIR toll-interleukin receptor domain, TIRAP TIR domain–containing adaptor protein, TRAM TRIF-related adaptor molecule, PK pharmacokinetics