Table 3.

Some currently registered and ongoing therapeutic trials in adult PSC

Therapy	Pathophysiologic target	Trial phase	Design	Lab inclusion criteria	Primary endpoint	Secondary endpoint
Bile acid based therapy
NorUDCA	UDCA derivative Unknown receptor	III	Double-blind RCT Multicenter	No (?)	ALP partial normalization	Histology
Cilofexor	FXR agonist	III	Double-blind RCT	ALT ≤ 8*ULN Bilirubin ≤ 2.0 mg/dL INR ≤ 1.4 Platelets ≥ 150,000	Histology	ΔALP Δother liver biochemistries ΔLSM (TE)  +  +
Therapy targeting PPAR
Seladelpar	Selective PPAR-δ agonist	II	Double-blind RCT	ALP ≥ 1.5*ULN and < 8*ULN Bilirubin ≤ 2*ULN ALT and AST ≤ 5*ULN Platelets ≥ 140,000	ΔALP at 24 w	LTX ΔMELD Hepatic decompensating  events HCC
Bezafibrate	PPAR-α agonist	III	Double-blind RCT	No	Proportion of patients reaching 50% reduction in itch intensity at 3 weeks	Δliver biochemistries Δautotaxin activity Δcholesterol, CK, creatinine
Therapy targeting gut microbiota
Vancomycin	Antibiotic	III	Double-blind RCT Multicenter	ALP ≥ 1.5*ULN	ALP normalization at 6, 12, 18, 21, 24 months	ΔTE at 18 months
Immune modulating therapy
Simvastatin	Immune modulating, receptor?	III	Double-blind RCT Multicenter	No	Overall survival; Listing for liver transplantation; Time to first varices bleeding or CCA, GBC, HCC	ΔALP Δbilirubin ΔMELD or ΔChild–Pugh MRCP progression ΔLSM (TE) or Δserum fibrosis markers Progression of symptoms, biliary dysplasia, colon cancer or dysplasia
Timolumab BTT1023 BUTEO trial	Anti-VAP-1 antibody	II	Open label	ALP > 1.5*ULN Stable ALP i.e. < 25% variation between screening visits 1 and 2	ALP 25% reduction by day 99
All-trans retinoic acid	FXR/RXR complex activation	II	Open label	ALP ≥ 1.5*ULN	ΔALP at 24 w	ALP > 1.5*ULN ΔALT Δbile acids ΔELF test ΔLSM (TE)
Sulfasalazine	Immune modulating	II	Double-blind RCT Multicenter	ALP ≥ 1.67*ULN Bilirubin ≤ 3 mg/dL INR ≤ 1.4 Platelets ≥ 100,000 MELD ≤ 10	ALP ≥ 1.5 at 22 w	Δother liver biochemistries ΔMayo risk score Symptoms
Vidofludimus calcium	Blocks IL-17 production	II	Open label	ALP > 1.5*ULN Indirect bilirubin < 1.2 *ULN	ΔALP at 3 and 6 months	Δother liver biochemistries IL-17 and IFNγ levels at 3 and 6 months

ALP alkaline phosphatase, ALT alanine transferase, CCA cholangiocarcinoma, ELF Enhanced Liver Fibrosis test, FXR farnesoid X receptor, GBC gallbladder cancer, HCC hepatocellular cancer, IFNγ interferon gamma, LSM liver stiffness measurements, MELD model for end-stage liver disease, PPAR peroxisome proliferator-activated receptor, RCT randomized controlled trial, RXR retinoid X receptor, TE transient elastography, ULN upper limit of normal, VAP-1 vascular adhesion protein-1