Novel treatments targeting immune‐related mechanisms in primary biliary cholangitis

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Abbreviations

ALP

alkaline phosphatase

AMA

antimitocondrial antibody

CTLA4

cytotoxic T lymphocyte antigen 4

Ig

immunoglobulin

IL

interleukin

mAb

monoclonal antibody

PBC

primary biliary cholangitis

UDCA

ursodeoxycholic acid

Primary biliary cholangitis (PBC), until recently named primary biliary cirrhosis,1 is a chronic disease of putative autoimmune origin that results in progressive intrahepatic cholestasis that later develops into end‐stage liver disease. A better understanding of disease progression has shown different processes along the time course at which therapeutic interventions should be aimed: from the failure of immunoregulatory checks at the incipient stages to fibrosis and parenchymal remodeling at later stages (Fig. 1). At the outset, it should be emphasized that these therapeutic strategies are not mutually exclusive, especially as different underlying disease mechanisms do coincide. For such strategies to be implemented, better biomarkers—serological, biochemical, and histological—to define disease stage are needed.

Figure 1.

Disease stage‐based approach to novel PBC therapeutics. Abbreviation: BEC, biliary epithelial cells.

In this review, we cover recent advances in research that have yielded numerous agents currently at different stages of the drug pipeline (Table 1), focusing on those targeting immune‐related mechanisms in PBC.

Table 1.

Active and Recently Run Clinical Trials in PBC

Drug Name	Class of Drug	Rationale	Phase of Development
INT 767	TGR5 agonists	Dual FXR and TGR5 agonist is shown to affect energy metabolism, glucose homeostasis, bile composition/secretion, and inflammation	Phase 1 (recruiting)
FFP104	Anti‐CD40	CD40 plays a key role in CD4+ T cell priming, B cell terminal maturation, and Ig class‐switch recombination	Phase 1‐2 (recruiting)
Bezafibrate, fenofibrate	PPAR‐α	Improvement of hepatic inflammation through PPAR‐α and MDR3	Phase 2 (recruiting)
MBX‐8025	PPAR‐γ	Activation of PPAR‐γ in stellate cells reverses their activation and might be involved in fibrosis regeneration	Phase 2 (recruiting)
Rituximab	Anti‐CD20	B‐cell‐depleting therapy showed to reduce fatigue in pilot study in PBC; endpoint is reduction of fatigue	Phase 2 (active)
Lopixibat	ASBT inhibitors	Apical sodium‐dependent bile acid transporter inhibitor reduces bile acid accumulation in the liver; trial endpoint was reduction of pruritus	Phase 2 (closed)
NI‐08091	Anti‐CXCL10	The chemokine CXCL10 plays an important role in T cell trafficking by binding CXCR3, highly expressed on effector T cells, that drives infiltration of inflammatory lymphocytes into the liver	Phase 2 (closed)
Ustekinumab	Anti‐IL‐12/IL‐23	Blockade of IL‐12/IL‐23 pathway, key player in the effector mechanisms that lead to biliary destruction, could alleviate inflammation in PBC	Phase 2 (closed)
Obeticholic acid (OCA)	FXR agonists	Bile acid shown anticholestatic, anti‐inflammatory, and antifibrotic effects in clinical studies, through the activation of the FXR	FDA filing phase 3 (confirmatory trial, recruiting)
Abatacept	Chimeric CTLA4	Fusion protein of the extracellular domain of CTLA4 and human IgG1, which binds to CD80 and CD86 molecules on the APC and prevents the costimulatory signal being delivered to the T cell that is needed for an immune response	Phase 4 (recruiting)

Abbreviations: ASBT, apical sodium‐dependent bile acid transporter; FXR, farnesoid X receptor; MDR3, multidrug resistance protein 3; PPAR, peroxisome proliferator‐activated receptor; TGR5, G‐protein‐coupled bile acid receptor Gpbar1.

Dacetuzumab/Lucatumumab (Anti‐CD40)

CD40 is expressed by B cells and facilitates their antigen presentation role to T helper cells. It binds to CD40L (CD154) on T cells to induce B cell proliferation, antibody class switching, and differentiation into plasma cells. It is of interest that the CD40 gene is located in the X chromosome, since major defects of sex chromosomes were found in patients with PBC.2, 3, 4 Interestingly, it has recently been demonstrated that epigenetic silencing of the CD40L promoter in CD4⁺ T cells correlates with the higher levels of immunoglobulin M (IgM) seen in PBC patients.5 CD40 is expressed on other antigen‐presenting cells including dendritic cells and macrophages, and activation of the latter by interaction with CD40L on T cells stimulates macrophages to produce interleukin (IL)‐12 and skew T helper cell into Th1 phenotype. In cholangiocytes, CD40 signaling also augments Fas‐dependent cell death.6

Administration of anti‐CD40L in murine models of autoimmune cholangitis reduces liver inflammation and lowers the levels of antimitocondrial antibody (AMA). A study of the safety, tolerability, and pharmacodynamics of dacetuzumab/lucatumumab, a CD40 antagonist, in patients with PBC is currently ongoing (Clinical Trial ID: NCT02193360).

Rituximab (Anti‐CD20)

The role of B cell–mediated antigen presentation in T cell autoimmunity, the presence of AMA in most patients with PBC, and the suggested suppressive effects of B cells on regulatory T cells have all given an impetus for B cell–depleting therapies. The use of antibodies against the human B cell surface protein CD20 represents the most advanced therapeutic approach among the B cell–depleting armamentarium for the treatment of autoimmune disorders. Rituximab is a mouse–human chimeric anti‐CD20 monoclonal antibody (mAb) designed for B cell depletion in humans. Its safety and efficacy as a therapeutic agent has been initially demonstrated in the treatment of non‐Hodgkin's B cell lymphoma and chronic lymphocytic leukemia, and subsequently in some autoimmune disorders such as granulomatosis with polyangiitis, microscopic polyangiitis, and rheumatoid arthritis.7

In vivo depletion of B cells gave controversial results. In xenobiotic‐induced autoimmune cholangitis mouse models treatment with anti‐CD20/CD79 increased the liver T cell infiltrates and the levels of proinflammatory cytokines with the development of a more severe form of cholangitis than control.8 In young dominant‐negative transforming growth factor‐βRII mouse models, anti‐CD20 therapy significantly alleviated the liver inflammation and reduced the bile duct damage.9

A pilot study on rituximab in humans was carried out in 2013. Fourteen patients with PBC refractory to ursodeoxycholic acid (UDCA) received two rituximab infusions (1000 mg) 2 weeks apart. Effective B cell depletion was observed in 13 patients (1 patient withdrew), including 3 who developed human anti‐chimeric antibodies. Alkaline phosphatase (ALP) normalization and/or ≥25% improvement was observed in three patients (23%) at 6, 12, and 18 months. Significant reductions in median ALP (from 259 U/L at baseline to 213 U/L at 6 months; median decrease, 16%) and serum IgM and AMA levels were observed at 6 months.10 Currently, a phase 2 trial to assess the efficacy of rituximab in reducing fatigue is ongoing in the United Kingdom.11

MDX 1100 and NI‐08091 (Anti‐CXCL10)

C‐X‐C motif chemokine 10 (CXCL10) is a chemokine secreted by several cell types including monocytes, endothelial cells, and fibroblasts in response to interferon‐γ. CXCL10 elicits its effects by binding to C‐X‐C Motif Chemokine Receptor 3 (CXCR3), a chemokine receptor that is highly expressed on effector T cells and plays an important role in T cell trafficking and function. CXCL10 and CXCR3 levels are consistently found to be upregulated in serum and liver of patients suffering from inflammatory hepatic disease, including PBC; indeed, CXCR3 is considered the main chemokine receptor driving infiltration of inflammatory lymphocytes into the liver.12 In animal models of liver disease, it has been shown that CXCL10 neutralization reduces inflammation and fibrosis. Altogether, these data suggest a potential role for CXCL10 as a therapeutic target in PBC.13

However, the open‐label phase 2 study of NI‐08091, a fully human IgG1 mAb, which binds with high affinity to human CXCL10, but not to the other CXCR3 ligands CXCL9 and CXCL11, failed to demonstrate the therapeutic benefit. Twenty‐nine patients with an incomplete response to UDCA received six consecutive intravenous administrations of NI‐08091 (10 mg/kg) every 2 weeks. NI‐08091 administration did not lead to a significant reduction in any of the liver function tests over time (unpublished data).

Ustekinumab (Anti‐IL‐12)

Data from genetic studies of patients with PBC, murine models, and in vitro experiments have identified the IL‐12 signaling pathway as a key player in the effector mechanisms that lead to biliary destruction.14, 15 For this reason, great hopes have been pinned on ustekinumab, a mAb against the p40 subunit. However, a recently concluded study including 20 patients with PBC and an inadequate response to UDCA therapy, who were administered 90 mg subcutaneous ustekinumab at weeks 0 and 4, then every 8 weeks through week 20, while showing a modest decrease in ALP (median ALP reduction from baseline to week 28 was 12.1%), has failed to establish a proof of concept for its efficacy.16

Abatacept (Cytotoxic T Lymphocyte Antigen 4 Immunoglobulin)

Activated T cells, particularly CD8 T cells, play a critical role in biliary cell destruction. Under physiological conditions, T cell activation involves the major histocompatibility complex and a set of costimulatory molecules, including a receptor on T cells termed cytotoxic T lymphocyte antigen 4 (CTLA4). Signaling by CTLA4 has the potential to modulate costimulation and induce inhibitory signals. The efficacy of CTLA4‐Ig to inhibit the manifestations of cholangitis, including AMA production, intrahepatic T cell infiltrates, and bile duct damage, has been shown in a murine model of cholangitis.17 Abatacept is a fusion protein of the extracellular domain of CTLA4 and human IgG1, which binds to CD80 and CD86 molecules on the antigen‐presenting cells and prevents the costimulatory signal being delivered to the T cell that is needed for an immune response. The ongoing phase 4 trial of abatacept, currently indicated in rheumatoid arthritis, aims to determine its efficacy in patients with PBC who do not respond adequately to UDCA (NCT02078882).

Conclusion

The evolving landscape in PBC with several novel disease‐modifying agents currently in development, clinical tools allowing patient's risk stratification and selection of those in need of second‐line therapies, will address in the future some of the unmet clinical needs in the field. Essential for the development of new drugs in such disease with slow progression where reaching hard clinical endpoints is unfeasible in a reasonable time, is the identification of surrogate markers of endpoints acceptable to regulatory authorities. Trials on PBC up to now have adopted the improvement of the ALP as clinical endpoint by using different thresholds. This is based on the known prognostic value of ALP18, 19 that has therefore been proposed as surrogate marker of outcome. However, the ALP alone cannot be considered a satisfactory surrogate endpoint in clinical trials because it does not reflect the overall disease process. Recently, two composite scoring systems including liver function tests, albumin and platelet count, have been developed by two independent groups.20, 21 They predict the risk of overall and liver‐related death within 5, 10, or 15 years with high accuracy; efforts are ongoing to explore their validity as future trial outcome measures.