Table.
Anti-IL-6 agents in the clinical drug development pipeline
| Route | Target | Conditions and phase of development | Comment | |
|---|---|---|---|---|
| Biologics | ||||
| Clazakizumab | Intravenous | IL-6 (site 1) | Rheumatoid arthritis and antibody-mediated rejection (renal transplantation; phase 2) | Multiple phase 2 COVID-19 studies recruiting, most not placebo-controlled; phase 2 study in psoriatic arthritis showed no dose effect |
| Sirukumab | Subcutaneous | IL-6 (site 1) | Depression (phase 2) | Phase 3 study in rheumatoid arthritis discontinued (increased rate of respiratory tract infections); phase 2 study in lupus nephritis discontinued |
| Siltuximab | Intravenous | IL-6 (site 1) | Castleman disease (approved); multiple myeloma and amyloid light-chain amyloidosis (phase 2) | Multiple phase 2 COVID-19 studies recruiting |
| Olokizumab | Subcutaneous | IL-6 (site 3) | Rheumatoid arthritis (phase 3) and COVID-19 (phase 2 and 3) | Phase 2 study in Crohn's disease discontinued because of delay in timelines |
| Tocilizumab | Subcutaneous and intravenous | IL-6R | Rheumatoid arthritis, juvenile idiopathic arthritis, Castleman disease, giant cell arteritis, cytokine release syndrome, and Takayasu's arteritis (approved); COVID-19 and neuromyelitis optica (phase 2) | Prospective, double-blind RCTs showed no mortality benefit in COVID-19; mixed results in open-label trials in COVID-19; high-dose group of phase 2 study in systemic lupus erythematosus stopped on safety grounds |
| Sarilumab | Subcutaneous | IL-6R | Rheumatoid arthritis (approved); COVID-19 (phase 3) | Unsuccessful in COVID-19 so far |
| Vobarilizumab | Subcutaneous | IL-6R | Rheumatoid arthritis and systemic lupus erythematosus (phase 2) | Progressing to phase 3 in rheumatoid arthritis despite missing primary endpoint (difference in ACR20 response at week 12) in phase 2 |
| Olamkicept | Intravenous | IL-6 and sIL-6R | Inflammatory bowel disease (phase 2) | Inhibitor of trans-signalling |
| Small-molecule inhibitors | ||||
| Tofacitinib | Oral | JAK1, JAK2, and JAK3 | Rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, and Crohn's disease (approved); psoriatic arthritis, psoriasis, alopecia areata, and ulcerative colitis (phase 3); scleroderma (phase 2) | Multiple phase 2 COVID-19 studies recruiting; clinical benefit might reflect inhibition of cytokines other than IL-6 |
| Ruxolitinib | Oral | JAK1 and JAK2 | Myelofibrosis and polycythaemia rubra vera (approved); graft-versus-host disease, polycythaemia rubra vera, vitiligo, and atopic dermatitis (phase 3); acute myeloid leukaemia, chronic lymphocytic leukaemia, essential thrombocythaemia, haemophagocytic syndrome, and bronchiolitis obliterans syndrome (phase 2) | Multiple phase 1 and 2 and one phase 3 COVID-19 studies recruiting; clinical benefit might reflect inhibition of cytokines other than IL-6 |
| Baricitinib | Oral | JAK1 and JAK2 | Rheumatoid arthritis (approved); juvenile idiopathic arthritis, systemic lupus erythematosus, alopecia areata, psoriaisis, and uveitis (phase 3); COVID-19 (phase 2 and 3); giant cell arteritis (phase 2) | Phase 2 trials in COVID-19 completed; prospective RCT data for COVID-19 not yet available |
| Filgotinib | Oral | JAK1 | Rheumatoid arthritis, Crohn's disease, and ulcerative colitis (phase 3); psoriatic arthritis, ankylosing spondylitis, lupus nephritis, and Sjogren's syndrome (phase 2) | Selective for JAK1; approval by the US Food and Drug Administration for use in rheumatoid arthritis denied on safety grounds |
| Upadacitinib | Oral | JAK1 | Rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Takayasu's arteritis, giant cell arteritis, Crohn's disease, ulcerative colitis, and atopic dermatitis (phase 3) | Selective for JAK1 |
| Abrocitinib | Oral | JAK1 | Atopic dermatitis (phase 3) | Selective for JAK1 |
| Decernotinib | Oral | JAK3 | Rheumatoid arthritis (as VX-509; phase 3) | Specific for JAK3 |
Status as of Jan 31, 2021. Phase 1 studies not listed. IL-6=interleukin-6. IL-6R=interleukin-6 receptor. RCT=randomised controlled trial. sIL-6R=soluble interleukin-6 receptor.