Table 1.
Main findings related to the novel drugs in PBC and PSC.
| Drug | Mechanism of action | Reference and ClinicalTrials.gov identifier | Study design | Treatment duration | Population | Findings |
|---|---|---|---|---|---|---|
| OCA | FXR agonist | Nevens et al.19
(POISE trial) NCT01473524 |
RCT UDCA+OCA versus UDCA+placebo |
1 year | 216 PBC with incomplete response to UDCA | In OCA-treated patients: significant improvement in ALP, total bilirubin; reduced CRP, interleukin-12, cleaved cytokeratin 18, IgA and IgG levels; decrease in HDL and triglycerides; increased pruritus |
| OCA | Kowdley et al.37
NCT00570765 |
RCT OCA monotherapy versus placebo |
12 weeks | 59 PBC | In OCA-treated patients: ALP reduction; increased pruritus; better tolerability with 10 mg/day dosing compared with 50 mg/day; benefit on liver function, hepatocellular damage and cholestasis; increased glutathione and osteopontin |
|
| OCA | Kowdley et al.37 NCT02177136 | RCT OCA versus placebo |
24 weeks | 77 PSC | In OCA-treated patients: significant reduction in ALP independent of UDCA use; increased pruritus |
|
| ATRA | Permissive activator of the nuclear receptor FXR/RXR | Assis et al.39
NCT01456468 |
Open-label pilot study ATRA+UDCA |
12 weeks | 15 PSC with incomplete response to UDCA | Reduction in ALT and C4 levels; no significant reduction in ALP |
| NGM282 | FGF 19 mimetic | Mayo et al.40
NCT02026401 |
RCT NGM282+UDCA versus Placebo+UDCA |
28 days | 45 PBC with pruritus | In treatment group: significant reduction in ALP levels; well tolerated, only minor GI side effects |
| NGM282 | Mayo et al. 40NCT02704364 |
RCT NGM282 versus placebo |
12 weeks | 62 PSC | In treatment group: decrease in levels of serum bile acids, aminotransferases and markers of fibrosis; failed to reduce ALP levels (primary endpoint) |
|
| Bezafibrate | Pan PPAR agonist | Corpechot et al.41
(BEZURSO trial) NCT01654731 |
RCT UDCA+ Bezafibrate versus UDCA+placebo |
2 years | 100 PBC with incomplete response to UDCA | In treatment group: decreased ALP and other liver biochemistries; improvement in markers of fibrosis; improvement in pruritus; |
| Bezafibrate | Reig et al.42 | Open label: bezafibrate + UDCA | Median treatment time 38 months | 48 PBC with incomplete response to UDCA | decreased ALP and other liver biochemistries; older age and lower liver stiffness score predicted response; improvement in pruritus; reduction in UK PBC risk score |
|
| Fenofibrate | PPARα agonist | Levy et al.43
NCT00575042 |
Open label: fenofibrate + UDCA | 48 weeks | 20 PBC with incomplete response to UDCA | Reduction in ALP, AST and IgM levels |
| Fenofibrate | Dejman et al.44
NCT01142323 |
Open label: fenofibrate |
6 months | 8 PSC | Significant reduction in ALP and ALT; no significant change in Mayo risk score; |
|
| Fenofibrate and bezafibrate | PPARα agonists | Lemoinne et al.45 | Open label: fenofibrate | 6–12 months | 15 PSC with incomplete response to UDCA | ALP, GGT and ALT decreased significantly; no serious adverse events |
| Seladelpar | Selective PPARδ agonist | Jones et al.46
NCT02609048 |
RCT seladelpar+UDCA versus placebo+UDCA |
12 weeks | 41 PBC with incomplete response to UDCA | In treatment group: complete normalization of ALP in five patients who completed 12 weeks of therapy; early termination due to significant increases in liver aminotransferases in three patients |
| Seladelpar | Hirschfield et al.47
NCT02955602 |
RCT, open label, dose ranging |
8 weeks | 116 PBC with incomplete response to UDCA | Interim results: reduction in ALP; no serious adverse events or transaminase elevation in an interim analysis at 12 weeks |
|
| norUDCA | Sidechain-shortened derivative of UDCA | Fickert et al.48
NCT01755507 |
RCT norUDCA versus placebo |
12 treatment weeks + 4-week follow up | 161 PSC | In treatment group: significant dose-dependent reductions in ALP levels; favorable safety profile |
| Rituximab | Monoclonal antibody against CD20; B-cell depletion | Tsuda et al.49
NCT00364819 |
Open label | 15 days | 6 PBC with incomplete response to UDCA | Significant reduction in ALP levels; transient decreases in memory B-cell and T-cell frequencies |
| Rituximab | Myers et al.50 | Open label | 6 months | 14 PBC with incomplete response to UDCA | Selective B-cell depletion, significant decrease in autoantibody production; limited biochemical efficacy |
|
| Ustekinumab | Monoclonal antibody against IL-12 and IL-23 | Hirschfield et al.51
NCT01389973 |
Open-label proof-of-concept study |
28 weeks | 20 PBC with incomplete response to UDCA | Failed to meet primary endpoint of reduction in ALP levels; no serious adverse events |
| Abatacept | Monoclonal antibody that targets CD80 and CD86 on antigen presenting cells and interferes with T-cell activation | Liu et al.52
NCT02078882 |
Open label | 24 weeks | 19 PBC with incomplete response to UDCA | No significant changes in ALP, ALT, bilirubin, albumin, immunoglobulins, or liver stiffness; well tolerated |
| Infliximab | Monoclonal antibody against TNF-α | Hommes et al.53 | RCT Infliximab versus placebo |
52 weeks | 24 PSC | In treatment group: failed to demonstrate efficacy: no clinical or histologic benefit |
| Simtuzumab | Humanized IgG4 monoclonal antibody against LOXL2 | Muir et al.54
NCT01672853 |
RCT Simtuzumab versus placebo |
96 weeks | 234 PSC | In treatment group: failed to meet primary endpoint of reduction in hepatic collagen concentration; no significant reduction In ALP levels; well tolerated |
| Vancomycin and metronidazole | Antibiotics; manipulation of gut microbiome: antimicrobial and immunomodulation effects |
Tabibian et al.55
NCT01085760 |
RCT, vancomycin (125 mg or 250 mg) versus metronidazole (250 mg or 500 mg) |
12 weeks | 35 PSC | Primary endpoint of reduction in ALP levels was seen in the vancomycin groups (low-dose and high-dose vancomycin); reduction in the PSC Mayo risk score in the low-dose vancomycin and low-dose metronidazole groups; decrease in pruritus with high-dose metronidazole; significant decrease in total bilirubin with low-dose metronidazole |
| Vancomycin | Antibiotic; manipulation of gut microbiome: antimicrobial and immunomodulation effects |
Rahimpour et al.56
NCT02605213 |
RCT, vancomycin versus placebo |
12 weeks | 29 PSC | In treatment group: significant decrease in ALP levels and PSC Mayo Score; significant decrease in symptoms: fatigue, pruritus, diarrhea and anorexia |
| Rifaximin | Antibiotic; manipulation of gut microbiome: antimicrobial and immunomodulation effects |
Tabibian et al.57
NCT01695174 |
Open-label pilot study |
12 weeks | 16 PSC | No significant changes in ALP, GGT, bilirubin or fatigue impact scale |
| Fecal microbiota transplantation | Manipulation of gut microbiome | NCT02424175 | Open-label pilot study |
12 weeks | 10 PSC with IBD | Decrease in ALP levels in post-FMT patients; no adverse events |
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ATRA, all-trans retinoic acid; C4, complement 4; CRP, C-reactive protein; FGF 19, fibroblast growth factor 19; FMT, fecal microbiota transplantation; FXR, farnesoid X receptor; GGT, gamma-glutamyltransferase; GI, gastrointestinal; HDL, high-density lipoprotein; IBD, inflammatory bowel disease; IgA, immunoglobulin A; IgG, immunoglobulin G; IgM, immunoglobulin M; IL-12, interleukin 12; IL-23, interleukin 23; LOXL2, lysyl oxidase-like 2; norUDCA, 24-norursodeoxycholic acid; OCA, obeticholic acid; PBC, primary biliary cholangitis; PPAR, peroxisome proliferator-activated receptor; PSC, primary sclerosing cholangitis; RCT, randomized clinical trial; RXR, retinoid X receptor; TNF-α, tumor necrosis factor alpha; UDCA, ursodeoxycholic acid.