Table 2.

Investigational Therapeutics for the Treatment of Primary Biliary Cholangitis

	Mechanism of Action	Clinical Trial Stage	Dosage		Primary Endpoints	Number of Participants	Final/Preliminary Results	Limitations/Adverse Events
PPAR agonists
Bezafibrate16	Pan-PPAR receptor agonist	Phase 3 (BEZURSO) completed	400 mg/day		Percentage of patients with complete biochemical response at 24 months -Normalization of AST, ALT, ALP, albumin, bilirubin, and prothrombin index.	100	Biochemical response in 31% of bezafibrate. ALP normalization in 67% of the patients in the bezafibrate group.	Creatinine level increased 5% from baseline in the bezafibrate group. Myalgia in 20% of patients in the bezafibrate group.
Fenofibrate17,18	PPAR-alpha agonist	Phase 2 completed	160 mg/day		Difference in median ALP at 1 year compared to baseline values.	20	Median serum ALP decreased significantly at 48 weeks from 351 (214-779) U/L at baseline to 177 (60-384) U/L at 48 weeks.	It was an uncontrolled, open-label pilot study. Heartburn was the most frequent adverse event.
Selaldepar22,42	PPAR-delta agonist	Phase 3 completed (ENHANCE)	5 mg titrated to 10 mg/day -10 mg/day		Composite response by month 3 that included: ALP <1.67 × ULN, ≥ 15% decrease in ALP, and total bilirubin ≤ ULN	112	Composite response was statistically significantly higher for the 5 mg (78.2%) and 10 mg (57.1%) arms than the rate for the placebo arm.	Early termination due to an unexpected histologic finding in a clinical trial of seladelpar for NASH. Most common adverse events: pruritus and abdominal pain.
		Phase 2 terminated	-Seladelpar/MBX-8025 50 mg -Seladelpar/MBX-8025 200 mg		Percentage change from baseline in ALP at 12 weeks	41	Changes in both seladelpar groups versus placebo were significant (P < .0001), no significant difference between seladelpar groups (P = ·1729).	Early termination due to increases in aminotransferases associated to treatment.
Elafibranor18	PPAR-alpha/delta agonist	Phase 2 completed	-Elafibranor 80 mg -Elafibranor 120 mg		Relative change from baseline is in serum ALP levels at week 12	45	Significant ALP reductions in elafibranor groups compared to placebo. Elafibranor 80 mg: -48.3% Elafibranor 120 mg: -40.6%	Reported adverse events: nausea, diarrhea, fatigue, and headache.
Saroglitazar23	PPAR-alpha/gamma agonist	Phase 2 completed (EPICS)	Saroglitazar magnesium 2 mg Saroglitazar magnesium 4 mg		Improvement in ALP levels after 16 weeks	37	Significant mean percentage reductions in ALP in the saroglitazar 4 mg (49%) and 2 mg (51%) groups.	Study drug discontinued in 4 patients from the study group due to aminotransferase increases.
FGF19 analogs
NGM28231	FGF19 analog	Phase 2 and 2b completed	Subcutaneous NGM282 doses of -0.3 mg -3 mg		Absolute change in ALP from baseline to day 28.	45	ALP levels were significantly reduced with NGM282, with LS mean difference from baseline of: -0.3 mg: –54.3 IU/L -3 mg: –69.3 IU/L	No significant change in the proportions of patients achieving ALP normalization or less than 1.67× ULN with NGM282 treatment.
FXR agonists
Tropifexor (LJN452)43	FXR agonist	Phase 2 completed	-30 µg -60 µg -90 µg		Fold change in serum GGT on day 28	61	Interim analysis showed a 72% decrease of GGT in treatment group at 4 weeks	-
Cilofexor (GS-9674)44	FXR agonist	Phase 2 terminated	-30 mg -100 mg		Safety and tolerability	71	Reduction ≥ 25% in ALP from baseline to week 12 in 17% on cilofexor 100 mg and 18% on 30 mg.	Pruritus leading to treatment discontinuation occurred in 7% of patients on cilofexor 100 mg
EDP-305	FXR agonist	Phase 2 completed (INTREPID)	-1 mg -2.5 mg		Proportion of patients with ≥ 20% reduction in ALP or ALP normalization at week 12.	68	Reduction ≥ 20% in ALP at week 12 in 45.2% (P = .106) on EDP-305 1 mg, 46.4% on 2.5 mg (P = .063), compared to 11.1% on placebo.	Treatment discontinuation due to pruritus in 3% for the 1 mg and 18% in the 2.5 mg EDP-305 groups.
ASC42	FXR agonist	Phase 2 ongoing	-5 mg -10 mg -15 mg		Percentage changes of ALP at day 85 compared with baseline.	-	Not yet recruiting	-
Other targets
Setanaxib (GKT137831, GKT831)	NOX1 and NOX4 inhibitor	Phase 2 completed	-400 mg twice daily 400 mg once daily		The percent change in serum GGT from baseline to week 24.	-	Results pending	Results pending
		Phase 2b/3 (TRANSFORM) recruiting	-1200 mg/day 1600 mg/day		Proportion of patients achieving biochemical response at week 52: ALP <1.67× ULN ALP reduction ≥ 15% from baseline Total bilirubin ≤1 xULN	-	Results pending	Results pending
Mesenchymal stem cells45	T-cell suppressant	Phase 1/2 completed	0.5 x 106cells/kg body weights 3 times at 4-week intervals		Serum ALP at weeks 0, 4, 8, 12, 24, 36, and 48 after treatment.	7	Significant decrease in serum ALP at 48 weeks from baseline (474.29 ± 223.26).	Small study population.
		Phase 2 recruiting	0.1-1 x 106 cells/kg body weight 3 times (week 0, 4, and 8)		Absolute change of ALP after 1 year of the initial stem cell treatment	-	Results pending
Etrasimod (APD334)	S1PR1, S1PR4, and S1PR5 agonist	Proof of concept study terminated			Change from baseline to week 24 in serum ALP.	-	No results available	Early termination due to sponsor decision.
Baricitinib	Janus Kinase (JAK) inhibitor	Proof of concept study terminated	-1 mg -2 mg		Change in ALP at week 12 from baseline	-	No results available	Early termination due to enrollment futility.
E6011	Anti-CX3CL1 antibody	Phase 2 terminated			Rate of ALP change from baseline at week 12.	-	No results available	Early termination due to lack of response after 12 weeks of treatment.
S-adenosyl-L-methionine (SAMe)46	Assists with detoxification and prevents oxidative stress	Phase 4	1200 mg daily for 6 months		Changes in PBC-40 questionnaire	24	Significant improvement in PBC-40 fatigue and pruritus, decreases in ALP, GGT, Total cholesterol in non-cirrhotic PBC patients	-
NI-0801	Human monoclonal antibody targeted against chemokine ligand 10 (CXCL10)	Phase 2a	6 infusions at 10 mg/kg		Liver function tests	29	No significant reduction in liver function tests	Headaches, fatigue, pruritus, diarrhea
Combined Antiretroviral Therapy (cART): Tenofovir-Emtricitabine (TDF/FTC), and Lopinavir-Ritonavir (LPRr)	Anti-retroviral therapy	Phase 2	TDF/FTC (300/200 mg daily) and LPRr (400/100 mg twice daily)		Reduction in alkaline phosphatase below 1.67 x the upper limit of normal, or normalization of total bilirubin	13	Significant improvement alkaline phosphatase but failure to meet the primary endpoint	Poorly tolerated due to significant gastrointestinal side effects
Pentoxifylline	Inhibits pro-inflammatory cytokines and anti-fibrotic effects	Pilot Study completed	400 mg 3 times daily		Change in serum ALP from baseline to 6 months	20	ALP levels were significantly reduced at month 6 (–57.3 IU/L) when compared to baseline.	It was a small open-label pilot.
Probiotics	Regulation of bile acid homeostasis	Phase 2 Not yet recruiting	One pack 3 times per day		Percentage of patients with ALP or GGT decreased by 20% from baseline at 6 months	-	Not yet recruiting	-
OP-724	Beta-catenin inhibitor	Phase 1 (NCT04047160)	140, 280, 380 mg/m2/4 hours twice a week		Occurrence of serious adverse events	12	Trial is ongoing

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; FGF19, fibroblast growth factor 19; FXR, farnesoid X receptor; GGT, gamma-glutamyl transferase; NASH, non-alcoholic steatohepatitis; NOX, nicotinamide adenine dinucleotide phosphate oxidase; PBC, primary biliary cholangitis; PPAR, peroxisome proliferator-activated receptor; S1PR, sphingosine 1-phosphate receptors; ULN, upper limit of normal.