Table 1.
Example constituents as candidates for combination disease modifying therapies in T1D
| Candidate constituent therapies for combination testing |
Proposed mechanism of action | Clinical experience in T1D (safe as monotherapies) |
Reference or source |
|---|---|---|---|
| Autoimmunity-disabling therapies | |||
| Anti-CD3 | Increases exhausted CD8 T cells | Phase 3 trial ongoing; significant difference in primary end point in multiple phase 2 trials | 11,22,45,51,90–93 |
| CTLA-4Ig | Inhibits signal 2 for T-cell activation and reduces follicular helper T cells | Significant difference in primary end point in phase 2 trial | 43,44,46,63,94 |
| Anti-CD40 | Blocks activation of CD4+ Teff cells by APC | Phase 2 trial ongoing | 95 |
| Antithymocyte globulin | Depletes T cells and other immune cells | Significant difference in primary end point in phase 2 trial | 18 |
| Anti-CD20 | Depletes activated B cells, some compensatory increase in T cells | Significant difference in primary end point in phase 2 trial | 96 |
| Anti-IL-12/23R | Inhibits Th17 cells | Phase 1B trial successful; phase 2 trial ongoing | 97 |
| Anti-IL-21 | Inhibits Teff proliferation and differentiation | Significant difference in primary end point in phase 2 trial monotherapy arm | 9 |
| LFA3Ig | Inhibits T-cell activation | Significant difference in primary end point in phase 2 trial | 98 |
| Inflammation-dampening therapies | |||
| Jak1 and Jak2 inhibitor | Inhibits differentiation and proliferation of Th1 and Th17 cells | Phase 2 trial ongoing; safety data from rheumatoid arthritis trials | 99 |
| Anti-tumor necrosis factor-α | Reduces inflammation; multicell target | Significant difference in primary end point in phase 2 trial | 100 |
| Anti-IL-6 | Reduces inflammation; multicell target | Phase 2 trial completed | 101 |
| Immune regulation-enhancing therapies | |||
| Proinsulin or GAD65 antigen (direct, nanoparticle, DNA) | Activates Tregs and/or modulates APCs | Multiple ongoing; significant difference in primary end point in phase 1B/2A trial with proinsulin or GAD-Alum | 102–104 |
| Lactococcus lactis (antigen+other) | Enhances Tregs | Significant difference in primary end point in phase 2A trial | 21,105 |
| Infused polyclonal Treg cells | Enhances Treg number and function | Phase 1 trial completed | 26–28 |
| Infused dendritic cells | Enhances tolerogenic antigen presentation | One phase 1 trial completed; second ongoing | 106; NCT04590872 |
| Ultra-low-dose IL-2 or IL-2 mutein | Enhances Treg number and function | Phase 1B trials successful; phase 2 trials ongoing | 30–33 |
| β-cell–directed therapies | |||
| Phenylalkylamine calcium channel blocker | Inhibits TXNIP and enhances β-cell survival | Phase 2 confirmatory trial ongoing | 107,108 |
| 2-Phenylaminopyrimidine derivative drug | Inhibits tyrosine kinases | Significant difference in primary end point in phase 2 trial (short term) | 109 |
| α-Difluoromethylornithine | Inhibits polyamine synthesis | Phase 1 trial ongoing | 110 |
| Disease-controlling therapies (as possible β-cell rest constituents in combination with an immunomodulator) | |||
| Amylin analog | Improves glucose control | Marketed with T1D indication | 111 |
| GLP-1 analogs | Enhances β-cell secretory capacity; reduces gut motility; inhibits glucagon release | Some difference in primary end point in phase 2 trials | 9,112–114 |