Table 2.
Results of non-UDCA therapeutic trials in PSC
| Therapy | References | N | Design | Lab inclusion criteria | Primary endpoint | Result ALP | Other results |
|---|---|---|---|---|---|---|---|
| Therapy targeting bile acids | |||||||
|
norUDCA UDCA derivative |
Fickert et al. [197] | 161 |
RCT Multicenter Phase II 12 weeks |
Bilirubin < 3.0 mg/dL | ΔALP at 12 weeks | Significant dose-dependent reductions in ALP; ΔALP (compared to placebo) − 12.3%, − 17.3% and − 26.0% in the 500, 1000 and 1500 mg treatment groups | Favorable safety profile (no increase in pruritus) |
|
NGM282 FGF-19 analogue |
Hirschfield et al. [107] | 62 |
RCT Phase II 12 weeks |
No | ΔALP at 12 weeks | No significant change in ALP |
Reduced BA Improved (reduced) fibrosis markers ELF test and PRO-C3 |
|
Obeticholic acid (OCA) FXR agonist AESOP trial |
Kowdley et al. [100] | 76 |
RCT Phase II 24 weeks |
ALP ≥ 2.0*ULN Bilirubin < 2.5*ULN |
ΔALP at 24 weeks | Significant reduction in ALP in the 5–10 mg treatment arm compared to placebo; ΔALP − 25% from baseline in the 5–10 mg treatment arm compared to ΔALP − 4.8% in placebo group; ΔALP − 14% vs − 25% in patients with and without UDCA at baseline in the 5–10 mg OCA arm | Increased pruritus; pruritus (severe pruritus) reported in 46% (8%), 60% (16%) and 67% (41%) in placebo, 1.5–3 mg and 5–10 mg groups; n = 15 drop-outs prior to 24 week assessment |
|
LUM001/maralixibat ASBT inhibitor CAMEO trial |
Completed; Results at clinicaltrials.gov | 27 |
Open label pilot 14 weeks |
ALT and AST ≤ 5*ULN | Δbile acid levels at 14 weeks | No reduction in ALP | ΔBA − 14.8 (− 38%) |
| Therapy targeting PPAR | |||||||
| Bezafibrate 400 mg/day | Mizuno et al. [121] | 7 |
Open-label pilot 6 months |
ALP > 1.5 × ULN | ΔALP at 6 months | ALP reduction with about 40% in 3/7 patients at 6 months | |
| Bezafibrate 400 mg/day | Mizuno et al. [122] | 11 |
Open-label pilot 12 weeks |
ΔALP at 12 weeks | ALP reduction at 12 weeks, ALP increase subsequent to treatment cessation | ||
| Bezafibrate 400 mg/day or fenofibrate 200 mg/day | Lemoinne et al. [123] | 20 | Retrospective study | ALP > 1.5 × ULN on UDCA | ΔALP | Reduced ALP after at least 6 months; 40% reached ALP < 1.5 × ULN | Reduced ALT and pruritus |
| Fenofibrate | Dejman et al. [124] | 8 |
Open label pilot 6 months |
ALP > 1.5 × ULN | ΔALP at 6 months | Significant ALP reduction: ΔALP − 43% |
Reduced ALT No significant effect on Mayo risk score |
| Therapy targeting gut microbiota | |||||||
| Vancomycin vs metronidazole | Tabibian et al. [137] | 28 |
RCT Phase II-III Multicenter 12 weeks |
ALP > 1.5*ULN | ΔALP at 12 weeks | Non-dose dependent ALP reduction in all 4 treatment arms (low vs high dose vancomycin or metronidazole) | |
| Vancomycin | Rahimpour et al. [138] | 29 |
RCT 12 weeks |
No | ΔMayo risk score | ALP reduction at 12 weeks; ΔALP − 18.2% | Reduced Mayo risk score |
| Metronidazole | Farkkila et al. 2004 [139] | 80 |
RCT Phase III 36 months |
No / not specified (possibly ALP or ALT > ULN) | ΔALP or other liver enzymes, Mayo risk score, symptoms or histology at 36 months | ALP reduction at 36 months; ΔALP − 52.4% vs − 37.7% in metronidazole + UDCA group vs UDCA + placebo group | Reduced Mayo risk score; higher proportion of patients showed histologic improvement of stage or grade |
| Minocycline | Silveira et al. [143] | 16 |
Open-label pilot 12 months |
ALP > 1.5*ULN | ΔALP at 12 months | ALP reduction at 12 months; ΔALP − 20% | Reduced Mayo risk score |
| Rifaximin | Tabibian et al. [140] | 16 |
Open-label pilot 3 months |
ALP > 1.5*ULN | 50% ALP reduction at 3 months | No significant ALP reduction | No significant reduction in bilirubin, GGT, Mayo risk score |
| Fecal transplantation | Allegretti et al. [41] | 10 |
Open-label pilot 24 weeks |
ALP > 1.5*ULN | ≥ 50% ALP reduction at week 24 | 30% (3/10) experienced a ≥ 50% decrease in ALP | |
| Immune modulating therapy | |||||||
| All-trans retinoic acid | Assis et al. [115] | 15 |
Open-label pilot 12 weeks |
ALP > 1.5 × ULN on UDCA | ΔALP − 30% at 12 weeks | Non-significant ALP reduction; 3/15 achieved ≥ 30% ALP reduction | Reduced ALT and C4; ALT returned to pre-treatment values after washout period |
| Infliximab | Hommes et al. [167] | 10 |
RCT 52 weeks |
ALP > 2*ULN | ≥ 50% ALP reduction at week 18 | Failed to demonstrate effect in the n = 6 treatment group | No change in histologic stage or symptom scores |
| Other or undefined targets | |||||||
|
Cenicriviroc Anti-inflammatory effects (CCR2/CCR5 antagonist) PERSEUS trial |
Completed, not published; results at clinicaltrials.gov | 20 |
Open label Phase II 24 weeks |
ALP > 1.5*ULN Bilirubin ≤ 2.0 mg/dL |
ALP (%Δ) | 50% (n = 10) of patients achieved ALP reduction to < 1.5*ULN at 24 weeks. Mean ALP reduction − 4.5% at 24 weeks. No patients achieved ALP normalization or 50% ALP reduction | |
|
Curcumin Anti-inflammatory effects, upregulation of PPAR-γ? |
Completed, not published | 15 |
Phase I–II Open-label |
ALP > 1.5*ULN | ALP 40% reduction or reduction to < 1.5*ULN | Results submitted to clinicaltrials.gov, but not posted | |
ALP alkaline phosphatase, ALT alanine transferase, ASBT apical sodium-dependent bile acid transporter, BA bile acids, C4 7 Alpha-hydroxy-4-cholesten-3-one (marker of bile acid synthesis), CCA cholangiocarcinoma, ELF Enhanced Liver Fibrosis test, FGF-19 fibroblast growth factor 19, FXR farnesoid X receptor, GGT gamma-glutamyltransferase, PPAR peroxisome proliferator-activated receptor, PRO-C3 marker of type III collagen formation, RCT randomized controlled trial, UDCA ursodeoxycholic acid, ULN upper limit of normal