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Obeticholic Acid: An Advanced Treatment For Primary Biliary Cholangitis (PBC)

Author: Dr. Shemin Shah A

Consultant Gastroenterologist Kozhikode district co-operative hospital

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Primary biliary cholangitis (PBC), previously referred to as primary biliary cirrhosis is an immune mediated cholestatic disease, It’s an increasing prevalence worldwide. It occurs more commonly in women than men at a ratio of 10:1, Large case series have reported prevalence rates of PBC ranging between 19 and 402 cases per million. However, serological studies of huge, presumably healthy cohorts demonstrate that AMA prevalence are often as high as 0.5%. PBC is a rare and progressive cholestatic liver disease. Several options are available for treatment of associated symptoms. But for management of PBC, UDCA remains first-line therapy. While OCA is being approved by FDA as a combination therapy in patients with inadequate response to UDCA, is the proven and effective second-line therapy. 


Primary biliary cholangitis (PBC), previously referred to as primary biliary cirrhosis, is an immune mediated cholestatic disease characterized by destruction of the tiny intrahepatic bile ducts; if left untreated, persistent inflammation and cholestasis cause biliary cirrhosis and end-stage liver disease [1]. It’s an increasing prevalence worldwide. It occurs more commonly in women than men at a ratio of 10:1 [2]. Large case series have reported prevalence rates of PBC ranging between 19 and 402 cases per million. However, serological studies of huge, presumably healthy cohorts show that AMA prevalence are often as high as 0.5%. Differences in estimates of PBC incidence and prevalence could also be thanks to the true difference in prevalence rates between populations or secondary to variable diagnostic criteria, case-finding methods, and physician awareness [3]. Anti-mitochondrial antibodies (AMAs) directed against the lipoyl domain of the E2 subunit of pyruvate dehydrogenase (PDC-E2) are detected in 95% of patients with primary biliary cirrhosis (PBC) and are present before the onset of clinical disease [4]. Many primary biliary cholangitis (PBC) patients are on ursodeoxycholic acid (UDCA) for months to even years have an inadequate response (Defined as a lack of normalization of alkaline phosphatase (ALP). Large longitudinal studies have shown that such a response is related to greater degrees of histologic progression. Within the Global PBC Study, approximately 40% of patients had an elevated risk of disease progression because of insufficient response of their ALP to UDCA therapy [5]. The identification of UDCA as PBC treatment was a monumental breakthrough in life science, but unfortunately approximately one-third of PBC patients lack an adequate biochemical response defined as a discount within the surrogate biomarker ALP to but 40% of baseline or but 1.67–2 times the upper limit of normal. OCA became the second approved treatment for PBC in 2016. Given the urgent need for extra treatments, it had been given a fast-track approval through a pathway for orphan drugs [6]. Obeticholic acid (OCA) may be a semi-synthetic hydrophobic steroid (BA) analogue that's highly selective agonist of farnesoid X receptor (FXR), a key nuclear BA receptor, which induces expression of gut-derived hormones, especially fibroblast protein 19. The resulting beneficial effects of OCA on glucose and lipid metabolism and particularly hepatic inflammation make it a candidate for the treatment of a spread of conditions including primary biliary cholangitis (PBC) and non-alcoholic steatohepatitis (NASH) [7].

Figure 1: Destruction of intrahepatic bile ducts in Primary Biliary Cholangitis

Diagnosis of PBC

Diagnosis of primary biliary cirrhosis (PBC) is based on established criteria that include cholestatic liver tests, a positive anti-mitochondrial antibody (AMA) test, and diagnostic or compatible liver biopsy findings. Up to 40% of patients with PBC are asymptomatic at the time of diagnosis and are identified after abnormal laboratory studies are found at the time of a routine health examination or during evaluation of unrelated complaints [8].

Figure 2: Progression of Primary Biliary Cholangitis in different stages

Liver Biochemical Tests

Most patients with PBC have abnormal liver tests including elevations of ALP, mild elevations of aminotransferase (alanine aminotransferase or aspartate aminotransferase) activity, and increased levels of immunoglobulins (mainly IgM). Some patients with PBC may have high alanine aminotransferase or aspartate aminotransferase activities associated with hyper-γ-globulinemia (elevated IgG). The magnitude of biochemical test elevations is loosely related to the severity of the disease [9]. In patients without cirrhosis, the degree of ALP elevation is related to the severity of ductopenia and inflammation on liver histology. The increase in aminotransferase and IgG levels reflects the degree of periportal and lobular neuroinflammation. The level of serum bilirubin reflects the severity of ductopenia and biliary piecemeal necrosis. Hyperbilirubinemia, hypergammaglobulinemia, hypoalbuminemia, and thrombocytopenia are indicators of the development of liver cirrhosis and portal hypertension. As in other chronic cholestatic disease, Serum cholesterol levels often elevated. As in other cholestatic diseases, serum cholesterol levels are often elevated [10].


AMA is found in 95% of PBC patients. Antinuclear antibody and anti-smooth muscle antibody are found in nearly half. In approximately 5% to 10% of the patients, AMA is absent or present only in low titer (≤1/80), when immunofluorescent techniques are used. The presence or absence of AMA, rather than the magnitude of antibody level, is most important in diagnosis. In some patients, antinuclear antibodies, particularly anti-glycoprotein 210 (anti-gp210) and/or anti-sp100, are present and may correlate with prognosis [11]; in some other AMA negative patients, antibodies against the major M2 components (PDC-E2 and 2-oxoglutaric acid dehydrogenase complex), are present using enzyme-linked immunosorbent assay or Western blotting techniques. There are five common strategies for detecting AMA in clinical practice, including indirect immunofluorescence, immunoblotting, enzyme immunoassay, Luminex beads, assay, and enzyme inhibition assay. The indirect immunofluorescence method has the lowest sensitivity, with over 15% of AMA-negative sera by indirect immunofluorescence showing reactivity to MIT3, a combination of three mitochondrial antigens [12].


Figure 3: Algorithm for the diagnosis of PBC. US, Ultrasound; MRCP, Magnetic Resonance Cholangiopancreatography; ALP, Alkaline Phosphatase; GGT, Gamma-glutamyl transferase; AMA, Anti-Mitochondrial Antibodies; ANA, Anti-Nuclear Antibodies [13]


Need of Additional Therapy

Historically, ursodeoxycholic acid (UDCA), a naturally occurring bile salt, was the only approved therapy for PBC. However, 40% of PBC patients do not respond to UDCA. Therefore, a large percentage of patients have disease progression to end-stage liver disease [14]. Many other agents have been trialed in treating this puzzling disease, including colchicine, fibrate, and methotrexate. However, these other therapies have not proven to be effective. Thus, there was a critical need for new pharmacotherapies to treat PBC and prolong survival from this disease. Obeticholic acid (OCA) is a new treatment for PBC that was recently approved by the Food and Drug Administration (FDA) [15].

Many novel therapeutic approaches are proposed to target patients with no or incomplete biochemical response to UDCA.  Among them, Peroxisome proliferator-activated receptor α agonists, farnesoid X receptor agonists, and biotherapies such as anti-cluster of differentiation-20, glucagon-like peptide-1 receptor agonists, and estrogen-α receptor agonists could be promising [16].

After UDCA, Obeticholic acid (OCA) was the second drug to successfully meet the primary endpoint of a large placebo-controlled phase III trial in PBC.

This goal was achieved both in patients with incomplete response or intolerance to UDCA and in UDCA-naive patients. OCA is a synthetic bile acid derivative with a high affinity for FXR, a nuclear receptor that closely regulates bile acid synthesis and secretion, and has been shown to mediate anti-inflammatory and anti-fibrotic effects [17].

Currently Available Treatment Options

Primary biliary cholangitis, being in nature an autoimmune disease, cannot be treated. Although the associated complications can be prevented and progression of disease can be slowed down by various available options. These include –

Ursodeoxycholic Acid (UDCA)

UDCA is been used widely after being approved by USFDA. Its use has changed the course of disease by decreasing the progression of disease to liver transplant. 

UDCA is a hydrophilic, synthetic bile acid which has been shown to protect cholangiocytes from inflammatory cholestatic injury induced by toxic hydrophobic bile acids such as chenodeoxycholic acid (CDCA) [18]. Prior to widespread use of UDCA, approximately 49% of patients with PBC progressed to cirrhosis, compared to 13% on long-term UDCA treatment [19]. Multiple studies have demonstrated that when UDCA is started in early stages of PBC, patient survival is comparable to the general population [20].

Standard of care for PBC includes treatment with 13–15 mg/kg/day of UDCA in divided doses was found to have significantly welled improvements in ALP level and Mayo risk score compared to the lower dose [21]. Biochemical response is typically determined after 6–12 months of continued treatment. Unfortunately, up to 40% of patients have an inadequate response to therapy [22]. Risk factors associated with decreased response rates are male gender and female younger than 45 years at the time of diagnosis [23]. Inadequate or absent response to UDCA is the strongest predictor of poor outcomes in PBC patients [24]

Obeticholic Acid (OCA)

OCA, a farnesoid X receptor (FXR) agonist, is a more potent analogue of CDCA. OCA helps in maintaining the bile acid homeostasis by decreasing bile acid synthesis and increasing bile acid flow (choleresis). In the liver, FXR agonists downregulate CYP7A1 resulting in decreased conversion of cholesterol to bile acids. In the ileum, FXR up-regulates fibroblast growth factor-19 (FGF-19) which then acts on the liver to further decrease bile acid synthesis [25].

In 2016, OCA was approved by the FDA as an additional therapy for patients with inadequate response to UDCA alone, and as a second-line agent for monotherapy in PBC patients intolerant to UDCA.

The drug was granted fast track designation and accelerated approval after two phase 2 trials and a phase 3 trial, the POISE study, demonstrated statistically significant outcomes with improvement in ALP levels [26]. The POISE study was a 12-month trial which assessed the efficacy of OCA, with the primary endpoints were ALP less than 1.67 times the upper limit of normal with a reduction of at least 15% from baseline, and a normal bilirubin [27]. Currently, the phase 4 COBALT trial (NCT02308111) is underway to confirm clinical benefit of OCA in PBC after prolonged use.

Approved dosing of OCA is dependent on the presence or absence of cirrhosis and is dosed at 5 mg daily initially in non-cirrhotic patients or in Child-Pugh class-A cirrhotic patients. The dose can be titrated up to a maximum of 10 mg daily in this patient group. On the other hand, Child-Pugh class-B or -C cirrhotic patients are dosed at a max of 5 mg weekly.

Treating the Symptoms

Besides, FDA approved medications for PBC, UDCA and OCA, have no impact on management of the associated symptoms. Therefore, the available treatments are also coupled with treating of the symptoms independently. The most common symptoms observed with PBC are pruritus and chronic fatigue, both of them can be debilitating and lead to decreased quality of life. And also, metabolic bone disease, fat soluble vitamin deficiency, hyperlipidemia, sicca complex and liver transplant being the others. Unfortunately, treatment options are limited and liver transplantation may be the only cure for many.


Chronic fatigue is the most common symptom of PBC. Many studies are being carried out investigating the medications, such as modafinil, rituximab and others for treating the fatigue associated with PBC were unable to prove their efficacy [28]. Further research is required in this area.


Pruritus is another common symptom of PBC, reported by up to 80% of patients. Currently, multiple medication options for PBC associated pruritus includes, Bile Acid Resins, rifampicin; and opioid antagonists, such as Naltrexone [29, 30]. But are associated with mild side effects.


PBC is a rare and progressive cholestatic liver disease. Several options are available for treatment of associated symptoms. But for management of PBC UDCA remains first-line therapy. While OCA is being approved by FDA as a combination therapy in patients with inadequate response to UDCA, is the proven and effective second-line therapy.


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