Novel Therapies for Managing Cholestasis

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Abbreviations

ALP

alkaline phosphatase

5‐ASA

5‐aminosalicylic acid

ATRA

all‐trans retinoic acid

CYP7A1

cholesterol 7‐alpha‐hydroxylase

FDA

US Food and Drug Administration

FGF

fibroblast growth factor

FXR

farnesoid X receptor

HNF4

hepatocyte nuclear factor 4

IL

interleukin

JAK

Janus kinase

LOXL2

lysyl oxidase‐like 2

LXR

liver X receptor

MDR3

multidrug resistance protein 3

N/A

not available

NF‐κB

nuclear factor‐kappa‐light‐chain‐enhancer of activated B cell

norUDCA

24‐norursodeoxycholic acid

NOX1/4

nicotinamide adenine dinucleotide phosphate oxidases 1 and 4

OCA

obeticholic acid

OL

open label

PBC

primary biliary cholangitis

PDGF

platelet‐derived growth factor

PPAR

peroxisome proliferator‐activated receptor

PSC

primary sclerosing cholangitis

PXR

pregnane X receptor

RCT

randomized controlled trial

TGF‐beta

transforming growth factor beta

TLR4

toll‐like receptor 4

TNF‐α

tumor necrosis factor alpha

UDCA

ursodeoxycholic acid

VAP1

vascular adhesion protein

VDR

vitamin D receptor

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the most common chronic cholestatic liver diseases in adults. The underlying pathophysiology is marked by destruction of bile ducts, buildup of bile acids, and continuous inflammation, leading to hepatobiliary damage. Novel therapies for managing cholestasis have recently emerged. The new therapies target different receptors, interleukins (ILs), and cytokines involved in bile acid homeostasis and fibrosis (Table 1 and Fig. 1).

Table 1.

Main Mechanisms of Action of Novel Therapies for Cholestatic Liver Diseases

Class of Drug	Mechanisms of Action	Drugs
FXR agonists	Nuclear hormone receptor involved in the regulation of bile acid homeostasis Anticholestatic effects o Decrease bile acids synthesis o Decrease enteral absorption o Decrease hepatocyte uptake and increase secretion into bile o Increase conjugation of bile acids Anti‐inflammatory effects o Downregulation of NF‐κB pathway Possible antifibrotic effects	OCA ATRA Cilofexor (GS9674) LJN452 EDP‐305
FGF 19 mimetics	FXR activation leads to increased transcription of FGF 19, which inhibits bile acid synthesis via suppression of CYP7A1 NGM282 is a nontumorigenic FGF 19 derivative	NGM282
PPAR‐α agonists	Downregulation of HNF4  → decreased CYP7A1 activity Downregulation of NF‐κB → decrease in TNF‐α Upregulation of MDR3 → protect cholangiocytes against bile salt toxicity via stimulation of phosphatidylcholine secretion and bile acid excretion	Fenofibrate
Pan‐PPAR agonists	Downregulation of HNF4 → decreased CYP7A1 activity Downregulation of NF‐κB → decrease in TNF‐α Upregulation of MDR3 → increased secretion of phospholipids PXR agonist → further downregulation of CYP7A1 PPAR‐γ activation modulates lipid metabolism → insulin sensitization	Bezafibrate
PPAR‐δ agonists	Improve insulin sensitivity → decreased lipid accumulation in the liver Induce weight loss Reduce markers of inflammation Reduce stellate cell activation	Seladelpar
Dual PPAR‐α and ‐δ agonists	Improve insulin sensitivity → decreased lipid accumulation in the liver Induce weight loss Reduce markers of inflammation Reduce stellate cell activation	Elafibranor
NorUDCA	Side chain shortened derivative of UDCA that lacks a methylene group → leads to its passive absorption by cholangiocytes, production of bicarbonate, and creation of a less toxic environment Antifibrotic, antiproliferative, and anti‐inflammatory properties (animal models)	NorUDCA
Immunomodulatory drugs	Rituximab → monoclonal antibody targeting the CD20 antigen on B cells Abatacept → monoclonal antibody that targets CD80 and CD86 on antigen‐presenting cells and interferes with T cell activation Ustekinumab → monoclonal antibody against IL‐12 and IL‐23 Infliximab → monoclonal antibody against TNF‐α Baricitinib → JAK inhibitor	Rituximab Abatacept Ustekinumab Infliximab Baricitinib
Antifibrotic therapies	Simtuzumab → monoclonal antibody against LOXL2	Simtuzumab VDR agonists
NOX inhibitors	GKT831 → potent inhibitor of the NOX1/4, affect TGF‐beta/NF‐κB signaling/hedgehog/TLR4/PDGF; decreased liver injury, inflammation, and fibrosis	GKT831

Figure 1.

New therapies classification according to mechanism of action.

Ursodeoxycholic acid (UDCA) is the mainstay and first‐line therapy for PBC, with a recommended dosage of 13 to 15 mg/kg/day.1 However, roughly 40% of patients with PBC fail to demonstrate complete biochemical response to UDCA and are at risk for disease progression. Despite its efficacy in PBC, UDCA use in PSC is controversial and is not US Food and Drug Administration (FDA) approved.

Farnesoid X Receptor Agonists

Obeticholic acid (OCA) has received accelerated approval for patients with PBC with intolerance or incomplete response to UDCA. The PBC OCA International Study of Efficacy (POISE) trial demonstrated significant improvement in alkaline phosphatase (ALP) after 12‐month treatment with OCA, with an incremental benefit noticed when increasing the dose from 5 to 10 mg/day.2 The incidence of pruritus was significantly higher with increased doses; thus, dose up‐titration is recommended in clinical practice. Reduced doses are used in patients with Child B or C cirrhosis to prevent hepatic decompensation. These patients should be started at a dosage of 5 mg/week (as opposed to daily); the dosage may be up‐titrated to 5 mg twice a week and later to a maximum of 10 mg twice a week, if tolerated. Significant benefits on liver fibrosis and long‐term outcomes have not yet been demonstrated, although paired biopsy analysis in a small subset of patients who participated in the POISE trial suggests regression in fibrosis or nonprogression. In addition, OCA is under evaluation in PSC, with preliminary results demonstrating a similar safety and efficacy profile (NCT02177136).

Three other FXR agonists are being studied for PBC: cilofexor (GS9674), LJN452, and EDP‐305 (Table 2, ongoing studies for PBC). Cilofexor was also studied in patients with PSC, with promising results3 (Table 3, ongoing studies for PSC).

Table 2.

Ongoing Clinical Trials in PBC

Drug	Mechanism of Action	Design	N	Phase	Duration	Clinical Trial Number
Seladelpar 2, 5, 10 mg	PPAR‐δ agonist	OL	356	II/III	60 months	NCT03301506
Seladelpar 5‐10, 10 mg	PPAR‐δ agonist	RCT	240	III	52 weeks	NCT03602560
Saroglitazar	PPAR‐α and ‐γ agonist	RCT	36	II	16 weeks	NCT03112681
GKT137831	NADPH oxidase NOX1/NOX4 inhibitor	RCT	111	II	28 weeks	NCT03226067
OCA (hepatic impairment)	FXR agonist	RCT	50	IV	48 weeks + OL extension up to 3 years	NCT03633227
OCA (compensated cirrhosis)	FXR agonist	RCT	428	IV	10 years	NCT02308111
EDP‐305	FXR agonist	RCT	119	II	12 weeks	NCT03394924
Cilofexor	FXR agonist	RCT	71	II	12 weeks + 30 days	NCT02943447
Baricitinib	JAK inhibitor	RCT	52	II	12 weeks	NCT03742973
Emtricitabine, tenofovir disoproxil, and raltegravir (Canada)	Combination antiretroviral therapy	RCT	60	II	12 months + 12 months OL	NCT03954327
UDCA combined probiotics (China)	Combined Bifidobacterium and Lactobacillus	RCT	40	I/II	6 months	NCT03521297
Bezafibrate (Mexico)	PPAR‐α, ‐γ, and ‐δ	RCT	34	III	12 months	NCT02937012
Fenofibrate (China)	PPAR‐α agonist	RCT	72	I/II	12 months	NCT02965911
Fenofibrate (China)	PPAR‐α agonist	OL	200	III	48 weeks	NCT02823353
Fenofibrate (China)	PPAR‐α agonist	RCT	200	III	48 weeks	NCT02823366
Mesenchymal stem cell transplantation (China)	Stem cell therapy	RCT	140	N/A	12 months	NCT03668145
BCD‐085 (Russia)	Humanized monoclonal antibody against IL‐17	OL	30	II	24 weeks	NCT03476993
Medium‐dose UDCA (18‐22 mg/kg/day; China)	Bile acid	RCT	40	IV	12 months	NCT03345589
FFP104 (Europe)	CD40‐antagonist monoclonal antibody	OL	24	I/II	24 weeks	NCT02193360
Sublimated mare milk supplement (Kazakhstan)	Supplement	RCT	40	N/A	4 months	NCT03665519

Table 3.

Ongoing Trials for PSC

Drug	Mechanism of Action	Design	N	Phase	Duration	Clinical Trial Number
Sulfasalazine	5‐ASA modulates inflammatory response	RCT	42	II	22 weeks	NCT03561584
DUR‐928	Endogenous sulfated oxysterol, ligand of LXRs	RCT	40	II	4 weeks + 56 days observation	NCT03394781
Vidofludimus calcium	Small‐molecule inhibitor of dihydroorotate dehydrogenase	OL	30	II	6 months	NCT03722576
Umbilical cord mesenchymal stem cells	Stem cell therapy for immunomodulation	RCT	20	I/II	1 year	NCT03516006
Cilofexor	FXR agonist	RCT	400	III	96 weeks	NCT03890120
BTT1023	Anti‐VAP1	OL	23	II	120 days	NCT02239211
Vancomycin	Manipulation of gut microbiome	RCT	102	II/III	2 years	NCT03710122
HTD1801	UDCA+berberine (antioxidant supplement)	RCT	90	II	18 weeks	NCT03333928
NorUDCA (Europe)	Anticholestatic	RCT	300	III	2 years	NCT03872921

All‐trans retinoic acid (ATRA), which activates the nuclear receptor complex FXR‐Retinoid X receptor (RXR), was evaluated for PSC in a pilot study of UDCA+ATRA and was shown to significantly decrease alanine aminotransferase (ALT) and complement‐4 levels. However, reduction in ALP levels was not significant.4

Fibroblast Growth Factor 19 Mimetics

NGM282 has demonstrated significant reduction in ALP levels and other liver biochemistries when evaluated for PBC.5 Conversely, a phase II trial in PSC failed to demonstrate significant reduction in ALP levels, although it did decrease levels of serum bile acids, aminotransferases, and fibrosis markers (NCT02704364).

Peroxisome Proliferator‐Activated Receptor Agonists

Peroxisome proliferator‐activated receptor (PPAR) agonists occur in three isoforms, α, δ, and γ, and regulate bile acid homeostasis, lipid and glucose metabolism, and inflammation (Table 1). Overall, studies demonstrate that both bezafibrate (pan‐PPAR agonist) and fenofibrate (PPAR‐α agonist) used in combination with UDCA are associated with marked biochemical improvement in PBC.6, 7 Of significance, the BEZURSO (Bezafibrate in Combination with Ursodeoxycholic Acid in Primary Biliary Cholangitis) trial showed that 67% of patients receiving bezafibrate + UDCA normalized their ALP, and 31% achieved complete normalization of all liver biochemistries. In addition, a benefit in reducing pruritus is suggested by open‐label (OL) studies with bezafibrate and is under further evaluation.

A selective PPAR‐δ agonist, seladelpar, has also shown major improvement in ALP levels. Although its first trial was terminated early because of three patients experiencing elevation of aminotransferases,8 an open‐label study with lower doses demonstrated a significant reduction in ALP and a good safety profile (NCT02955602). Moreover, the drug appears to be safe in patients with cirrhosis, with similar anticholestatic and anti‐inflammatory effects as in patients without cirrhosis.

Elafibranor, a dual PPAR‐α and ‐δ agonist, was recently evaluated in patients with inadequate response to UDCA and was associated with a significant decrease in ALP levels and anti‐inflammatory markers.

Similarly, small, uncontrolled studies have also evaluated PPAR agonists in PSC with promising results.

24‐Norursodeoxycholic ACID

In a phase II clinical trial for patients with PSC, use of 24‐norursodeoxycholic acid (norUDCA) resulted in significant dose‐dependent reductions in ALP levels with an excellent tolerability profile.9 The highest dosage, 1500 mg/day, led to a 26% reduction in ALP from baseline. A phase III study is ongoing in Europe.

Other Novel Therapies

Immunomodulatory Drugs

Immunomodulation emerges as a potential option for cholestatic diseases, especially if implemented before significant disease progression. Unfortunately, several studies with immunomodulators have failed to meet endpoints of reduction in ALP or to provide significant clinical benefit, which can be in part related to the profile of treated patients: usually nonresponders to UDCA with advanced disease. These studies evaluated drugs such as rituximab, abatacept, ustekinumab, and infliximab. One ongoing phase II trial is evaluating the safety and tolerability of a Janus kinase (JAK) inhibitor, baricitinib, in PBC (NCT03742973).

Antifibrotic Therapies

The possibility of modulating fibrogenesis and altering the course of cholestatic diseases is exciting. As mentioned earlier, OCA has demonstrated antifibrotic properties in animal experiments and in a small subset of patients participating in the POISE trial. Simtuzumab, a monoclonal antibody against lysyl oxidase‐like 2 (LOXL2), was evaluated in a 2‐year phase 2 study for PSC and did not show a benefit in improving fibrosis or reducing PSC‐related clinical events.10 The FXR agonist cilofexor is under evaluation for PSC, with regression of fibrosis as a primary study endpoint.

NOX1/4 Inhibitor

GKT831 is a potent inhibitor of the nicotinamide adenine dinucleotide phosphate oxidases 1 and 4 (NOX1/4). Interim results of a phase 2 clinical trial showed that it significantly reduced ALP and gamma‐glutamyl transferase levels at week 6 in the group receiving 400 mg twice a day.

Manipulation of Gut Microbiome

The microbiome plays an important role in modulating the bile acid pool. Conversely, bile acids can also decrease the pool of bile‐sensitive bacteria and select a specific profile of gut microbiota. Therefore, several antibiotics have been studied for PSC. The best evidence points to vancomycin, which has led to reductions of ALP levels and PSC Mayo Risk Score. However, long‐term efficacy and safety remain unknown. A promising strategy involves altering the gut microbiome with fecal microbiota transplantation.

Conclusion

From FXR agonists to altering the composition of the gut microbiome, the potential options for treating cholestatic liver diseases have multiplied in recent years. Most of the new therapies are still undergoing evaluation in clinical trials and will potentially emerge as adjuvant or second‐line options for nonresponders to the FDA‐approved UDCA and OCA. Understanding the pathogenesis of PBC and PSC will continue to be important for the development of new therapies that target specific molecular pathways in cholestasis, inflammation, and fibrosis. Furthermore, it will help with personalizing therapies for individual patients.