Second-line treatment of primary biliary cholangitis: To whom, which molecule, and when

Table 1 Overview of the most commonly used qualitative binary scoring systems in primary biliary cholangitis patients treated with ursodeoxycholic acid

Name of scoring system	Duration of treatment (mo)	Type of PBC population	UDCA treatment response definition	Ref.
Rochester	6	American	ALP < 2 × ULN and Mayo Risk Score < 4.5	[18]
Barcelona	12	European	Decrease in ALP > 40% or ALP ≤ × 1 ULN	[19]
Paris-I	12	European	ALP < 3 × ULN and AST < 2 × ULN and bilirubin ≤ 1 mg/dL	[20]
Paris-II	12	European	ALP ≤ × 1.5 ULN and AST ≤ × 1.5 ULN and bilirubin ≤ 1 × ULN	[21]
Rotterdam	12	European	Bilirubin ≤ 1 × ULN and albumin ≥ 1 × ULN	[22]
Ehime	6	Asian	Decrease in GGT > 70% or GGT ≤ 1 × ULN	[23]
Toronto	24	American	ALP ≤ 1.67 × ULN	[24]
Xi’an	1	Asian	ALP ≤ 2.5 × ULN, AST ≤ 2 × ULN and total bilirubin ≤ 1 × ULN	[25]
Monza	12	European	GGT < 3.2 × ULN or ALP < 2 × ULN	[26]
Global PBC study group	12	International	Bilirubin ≤ 0.6 × ULN and ALP ≤ 1 × ULN	[17]

ALP: Alkaline phosphatase; AST: Aspartate aminotransferase; GGT: Gamma glutamyl transferase; mo: Months; PBC: Primary biliary cholangitis; UDCA: Ursodeoxycholic acid; ULN: Upper limit of normal.

Table 2 Overview of peroxisome proliferator-activated receptor agonists used in the treatment of primary biliary cholangitis

Name of PPAR agonist	Fibrate/non-fibrate	Isotypes of PPAR	Status of regulatory approval	Clinical results
Elafibranor	Non-fibrate	PPAR-α and PPAR-β/δ	Approved	Improvement of cholestasis
				Biochemical response and ALP normalization
				Reduction of pruritus
				Improvement of fatigue and sleep disturbance
Seladelpar	Non-fibrate	PPAR-β/δ	Approved	Improvement of cholestasis
				Biochemical response
				ALP normalization
				Reduction of pruritus
				Improvement of fatigue and sleep disturbance
Saroglitazar	Non-fibrate	PPAR-α and PPAR-γ	Phase 3 study complete	Improvement of cholestasis
				Biochemical response and ALP decrease
Bezafibrate	Fibrate	PPAR-α, PPAR-γ and PPAR-β/δ	Off-label	Improvement of cholestasis
				Biochemical response and ALP normalization
				Reduction of pruritus
Fenofibrate	Fibrate	PPAR-α	Off-label	Improvement of cholestasis
				Biochemical response and ALP normalization
				Reduction of pruritus

ALP: Alkaline phosphatase; PPAR: Peroxisome proliferator-activated receptor.

Table 3 Overview of drugs in clinical trials for primary biliary cholangitis

Drug name	Drug class	Therapeutic indication	Study phase
Tropifexor	FXR agonist	PBC	Phase 2 complete
Cilofexor	FXR agonist	PBC	Phase 2 complete
TQA3526	FXR agonist	PBC	Phase 3 ongoing
ASC42	FXR agonist	PBC	Phase 2 closed prematurely
Nor-UDCA	UDCA homolog	PBC	Phase 2 ongoing
Aldafermin	FGF-19 analogue	PBC	Phase 2 complete
Setanaxib	NOX 1/4 inhibitor	PBC	Phase 2b complete
Linerixibat	IBAT inhibitor	Pruritus in PBC	Phase 3 complete; FDA approved for pruritus in PBC
Maralixibat	IBAT inhibitor	Pruritus in PBC	Phase 2 complete
Volixibat	IBAT inhibitor	Pruritus in PBC	Phase 2b ongoing

FDA: Food and drug administration; FGF: Fibroblast growth factor; FXR: Farnesoid X receptor; IBAT: Ileal bile acid transporter; NOX1/4: Dual nicotinamide adenine dinucleotide phosphate oxidase 1/4; PBC: Primary biliary cholangitis; UDCA: Ursodeoxycholic acid.