Exemplary clinical trials in inflammatory, autoimmune, and inflammation-related diseases
| Study focus . | Disease . | Substance/intervention . | Molecular/cellular target . | Cell target . | Success/failure . | Study type . | Reference (year of publication) . |
|---|---|---|---|---|---|---|---|
| BTK inhibition in patients with severe COVID-19 | Severe COVID-19 | Acalabrutinib | BTK inhibition | B cells, platelets, monocytes, macrophages, neutrophils, dendritic cells | Positive (improvement of oxygenation); international confirmatory study ongoing | Single-center probatory trial | 157 (2020) |
| BTK | Rheumatoid arthritis | Spebrutinib (CC-292) | BTK inhibition | B cells, platelets, monocytes, macrophages, neutrophils, dendritic cells | Mixed (did not meet primary end points; but subgroup analysis might hold potential; downward trend in symptoms; furthermore, modulation of B-cell populations) | Multicenter phase 2a trial | 158 (2020) |
| JAK inhibition in skin inflammation | Atopic dermatitis | Tofacitinib | JAK inhibition | Ubiquitous | Positive (greater efficacy and early onset of effect) | Phase 2a trial | 159 (2016) |
| JAK inhibition in RA | RA | Filgotinib | JAK1 inhibition | Ubiquitous | Positive (regulation of biomarkers and correlation with disease activity) | Phase 2b trial | 160 (2020) |
| MS | MS | Evobrutinib | BTK inhibition | B cells, platelets, monocytes, macrophages, neutrophils, dendritic cells | Mixed positive (fewer enhancing lesions during weeks 12 to 24 compared with placebo but no difference in relapse rate or disability progression) | Multicenter phase 2 trial | 161 (2019) |
| MS | Highly active relapsing-remitting MS | Natalizumab | VLA-4 | HSPCs, T cells, B cells, monocytes, NK cells, eosinophils, neutrophils | Mixed: first failure (progressive multifocal leukoencephalopathy) and then reallowance | 162, 163 | |
| MS | Relapsing remitting multiple sclerosis | Firategrast | VLA-4 | HSPCs, T cells, B cells, monocytes, NK cells, eosinophils, neutrophils | Positive for phase 2 trial (imaging end points improved); awaiting phase 3 | Phase 2 | 164 (2012) |
| Enlimomab Acute Stroke Trial | Ischemic stroke | Enlimomab | ICAM-1 antibody (murine into human) | Endothelial cells, epithelial cells, vascular smooth muscle cells, certain leukocyte subsets | Negative (worse Modified Rankin Scale score in treated patients; more adverse events including infections) | 130 (2001) | |
| Crohn’s disease | Steroid-refractory Crohn’s disease | ICAM-1 antisense oligonucleotide (ISIS-2302) | Adhesion/outside-in signaling | Endothelial cells, epithelial cells, vascular smooth muscle cells, certain leukocyte subsets | Negative for primary end point: steroid-free remission (but treatment led to increased rate of glucocorticoid dose 0 mg prednisone equivalent) | 131 (2001) | |
| HALT-MI study | Myocardial infarction with direct primary angioplasty | Rovelizumab (= LeukArrest) | CD11/CD18 (humanized Ab) | Leukocytes | Negative (no infarct size reduction) | Multicenter placebo-controlled double blinded RCT | 132 (2002) |
| Meta-analysis for moderate to severe psoriasis | Psoriasis | Alefacept, efalizumab, etanercept, infliximab | LFA-1 (efalizumab), TNF-α (infliximab, etanercept), | Leukocytes (efalizumab); systemic (TNF) | Positive (infliximab > etanercept > efalizumab > alefacept). But increased SAEs in efalizumab trials. | Systematic review | 165 (2005) |
| Dry eye disease | Dry eye disease | Lifitegrast (LFA-1 antibody) | Adhesion | Leukocytes | Positive, but increased adverse events. | Multicenter RCT | 166 (2016) |
| Pneumonia | Pneumonia | Simvastatin | NETosis, chemotaxis | Positive (improved neutrophil function and improved SOFA scores compared with placebo) | RCT | 167 (2019) | |
| BMS-936559 study | Sepsis | Antiprogrammed cell death-ligand 1 antibody (hinders binding of PD-L1 to PD-1 and CD80) | Safe increased monocyte human leukocyte antigen-DR expression, but future randomized trials are needed | Placebo-controlled dose-escalation RCT | 168 (2019) | ||
| Sepsis | Severe sepsis | Polymyxin B hemoperfusion | Endotoxin elimination | Systemic | Negative for sepsis outcomes, but improved mHLA-DR expression in severe sepsis | RCT | 169, 170 (2018) |
| Crohn’s disease | Ulcerative colitis, Crohn’s disease | Madcam-1 receptor (α4β7 integrin) antibody | α4β7 inhibitor (Madcam receptor) | NK cells, eosinophils, T cells, B cells, and, to some extent, endothelial cells | Approved (vedolizumab); discontinued (abrilumab) | 154 | |
| RA | RA | TNF-α blocker | Systemic | Positive, but almost similar effectiveness to methotrexate | Meta-analysis | 171 (2012) | |
| Septic shock | Septic shock | TNF blocker (mAb) | Systemic | Negative. (No overall difference in mortality. Significant difference at day 3 reduction in mortality but no significant difference at day 28) | Multicenter RCT | 172 (1995) | |
| Sepsis | Sepsis | TNF blocker | Systemic | Positive (decreased risk of death) but emphasizes only modest effects with past results possibly negative because of underpowering | Meta-analysis | 173 (2014) |
| Study focus . | Disease . | Substance/intervention . | Molecular/cellular target . | Cell target . | Success/failure . | Study type . | Reference (year of publication) . |
|---|---|---|---|---|---|---|---|
| BTK inhibition in patients with severe COVID-19 | Severe COVID-19 | Acalabrutinib | BTK inhibition | B cells, platelets, monocytes, macrophages, neutrophils, dendritic cells | Positive (improvement of oxygenation); international confirmatory study ongoing | Single-center probatory trial | 157 (2020) |
| BTK | Rheumatoid arthritis | Spebrutinib (CC-292) | BTK inhibition | B cells, platelets, monocytes, macrophages, neutrophils, dendritic cells | Mixed (did not meet primary end points; but subgroup analysis might hold potential; downward trend in symptoms; furthermore, modulation of B-cell populations) | Multicenter phase 2a trial | 158 (2020) |
| JAK inhibition in skin inflammation | Atopic dermatitis | Tofacitinib | JAK inhibition | Ubiquitous | Positive (greater efficacy and early onset of effect) | Phase 2a trial | 159 (2016) |
| JAK inhibition in RA | RA | Filgotinib | JAK1 inhibition | Ubiquitous | Positive (regulation of biomarkers and correlation with disease activity) | Phase 2b trial | 160 (2020) |
| MS | MS | Evobrutinib | BTK inhibition | B cells, platelets, monocytes, macrophages, neutrophils, dendritic cells | Mixed positive (fewer enhancing lesions during weeks 12 to 24 compared with placebo but no difference in relapse rate or disability progression) | Multicenter phase 2 trial | 161 (2019) |
| MS | Highly active relapsing-remitting MS | Natalizumab | VLA-4 | HSPCs, T cells, B cells, monocytes, NK cells, eosinophils, neutrophils | Mixed: first failure (progressive multifocal leukoencephalopathy) and then reallowance | 162, 163 | |
| MS | Relapsing remitting multiple sclerosis | Firategrast | VLA-4 | HSPCs, T cells, B cells, monocytes, NK cells, eosinophils, neutrophils | Positive for phase 2 trial (imaging end points improved); awaiting phase 3 | Phase 2 | 164 (2012) |
| Enlimomab Acute Stroke Trial | Ischemic stroke | Enlimomab | ICAM-1 antibody (murine into human) | Endothelial cells, epithelial cells, vascular smooth muscle cells, certain leukocyte subsets | Negative (worse Modified Rankin Scale score in treated patients; more adverse events including infections) | 130 (2001) | |
| Crohn’s disease | Steroid-refractory Crohn’s disease | ICAM-1 antisense oligonucleotide (ISIS-2302) | Adhesion/outside-in signaling | Endothelial cells, epithelial cells, vascular smooth muscle cells, certain leukocyte subsets | Negative for primary end point: steroid-free remission (but treatment led to increased rate of glucocorticoid dose 0 mg prednisone equivalent) | 131 (2001) | |
| HALT-MI study | Myocardial infarction with direct primary angioplasty | Rovelizumab (= LeukArrest) | CD11/CD18 (humanized Ab) | Leukocytes | Negative (no infarct size reduction) | Multicenter placebo-controlled double blinded RCT | 132 (2002) |
| Meta-analysis for moderate to severe psoriasis | Psoriasis | Alefacept, efalizumab, etanercept, infliximab | LFA-1 (efalizumab), TNF-α (infliximab, etanercept), | Leukocytes (efalizumab); systemic (TNF) | Positive (infliximab > etanercept > efalizumab > alefacept). But increased SAEs in efalizumab trials. | Systematic review | 165 (2005) |
| Dry eye disease | Dry eye disease | Lifitegrast (LFA-1 antibody) | Adhesion | Leukocytes | Positive, but increased adverse events. | Multicenter RCT | 166 (2016) |
| Pneumonia | Pneumonia | Simvastatin | NETosis, chemotaxis | Positive (improved neutrophil function and improved SOFA scores compared with placebo) | RCT | 167 (2019) | |
| BMS-936559 study | Sepsis | Antiprogrammed cell death-ligand 1 antibody (hinders binding of PD-L1 to PD-1 and CD80) | Safe increased monocyte human leukocyte antigen-DR expression, but future randomized trials are needed | Placebo-controlled dose-escalation RCT | 168 (2019) | ||
| Sepsis | Severe sepsis | Polymyxin B hemoperfusion | Endotoxin elimination | Systemic | Negative for sepsis outcomes, but improved mHLA-DR expression in severe sepsis | RCT | 169, 170 (2018) |
| Crohn’s disease | Ulcerative colitis, Crohn’s disease | Madcam-1 receptor (α4β7 integrin) antibody | α4β7 inhibitor (Madcam receptor) | NK cells, eosinophils, T cells, B cells, and, to some extent, endothelial cells | Approved (vedolizumab); discontinued (abrilumab) | 154 | |
| RA | RA | TNF-α blocker | Systemic | Positive, but almost similar effectiveness to methotrexate | Meta-analysis | 171 (2012) | |
| Septic shock | Septic shock | TNF blocker (mAb) | Systemic | Negative. (No overall difference in mortality. Significant difference at day 3 reduction in mortality but no significant difference at day 28) | Multicenter RCT | 172 (1995) | |
| Sepsis | Sepsis | TNF blocker | Systemic | Positive (decreased risk of death) but emphasizes only modest effects with past results possibly negative because of underpowering | Meta-analysis | 173 (2014) |
Studies include data in which the target cell is unclear; inhibitors or blocking agents do not only target neutrophils.
Ab, antibody; BTK, Bruton tyrosine kinase; HSPCs, hematopoietic stem and progenitor cells; mAb, monoclonal antibody; mHLA-DR, monocyte HLA-DR; MS, multiple sclerosis; NK, natural killer; RA, rheumatoid arthritis; RCT, randomized controlled trial; SAE, serious adverse event; SOFA, Sequential Organ Failure Assessment; TNF, tumor necrosis factor.