Clinic Rev Allerg Immunol DOI 10.1007/s12016-014-8456-5
New Therapies for Primary Biliary Cirrhosis Annarosa Floreani & Irene Franceschet & Lisa Perini & Nora Cazzagon & M. Eric Gershwin & Christopher L. Bowlus
# Springer Science+Business Media New York 2014
Abstract Primary biliary cirrhosis (PBC) is a rare inflammatory liver disease for which ursodeoxycholic acid (UDCA) is the only therapy approved by the U.S. Food and Drug Administration. Patients with a biochemical response to UDCA therapy have a similar survival rate compared to the general population. However, up to 40 % of PBC patients do not achieve a complete response to UDCA, have an increased risk of liver-related death and liver transplantation, and represent a persistent medical need for new therapies. Several novel drugs have recently been studied and show potential efficacy in PBC. Obeticholic acid, a farnesoid X receptor agonist, has been tested in phase II trials and initial results after 1 year in a phase III international trial suggest that it may be effective in achieving a biochemical response in approximately 40 % of patients who do not completely respond to UDCA. Several small studies on fibrates have suggested that they may have efficacy, but larger studies are needed. Surprisingly, results of immunomodulators and biologics have not yet been able to demonstrate efficacy, but new approaches have shown promise in animal models and their translation to human clinical trials are awaited.
A. Floreani (*) : I. Franceschet : L. Perini : N. Cazzagon Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy e-mail: [email protected] M. E. Gershwin Division of Rheumatology, Allergy, and Clinical Immunology, University of California Davis, Davis, CA, USA C. L. Bowlus Division of Gastroenterology and Hepatology, University of California Davis, Davis, CA, USA
Keywords Primary biliary cirrhosis . Ursodeoxycholic acid . Obeticholic acid . Anti-TNF-α . CXCL10 monoclonal antibody . Budesonide . Fibrates
Introduction Primary biliary cirrhosis (PBC) is a chronic liver disease characterized by progressive immune-mediated destruction of the small-to-medium-sized bile ducts, resulting in chronic cholestasis, portal inflammation, and fibrosis that can lead to cirrhosis and, ultimately, liver failure [1]. PBC is a complex disease whose etiology is not completely understood. It is now widely accepted that PBC results from an environmental stimulus intervening on a genetically susceptible background, causing the loss of tolerance to mitochondrial self-antigens, evidenced by the presence of anti-mitochondrial antibodies (AMA) in more than 80 % of cases, and an immune response against intrahepatic biliary epithelial cells [2]. The autoimmune pathogenesis of PBC is supported by its epidemiological characteristics; the presence of highly specific autoantibodies in the serums of patients; and an inflammatory CD4+ and CD8+ T-cells infiltrate against the same self-antigens. In addition to the classic AMA, anti-nuclear antibodies (ANAs) are present in approximately 50 % of patients with two particular fluoroscopic patterns: nuclear-rim (against the glycoprotein 210 and nuclearporin 62) and multiple nuclear-dots (against the Sp100 and PML proteins) [3]. Further, PBCspecific autoantibodies to Kelch-like 12 and hexokinase have also been described [4]. Initially described in women with advanced disease, i.e., cirrhosis, the moniker primary biliary cirrhosis has become a misnomer as the clinical presentation has changed over the years with the majority of patients having mild disease at diagnosis [5, 6]. In addition to the life-threatening complications of cirrhosis, quality of life related to PBC includes
Clinic Rev Allerg Immunol
fatigue and pruritus, although symptomatology is not correlated with disease activity or severity. However, the presence of fatigue and pruritus at diagnosis in recent studies appears to identify a subgroup of patients with a disease that is less responsive to UDCA treatment and more prone to progress to cirrhosis and liver failure [7]. The coexistence of other autoimmune disorders is common including Raynaud’s phenomenon, Sjogrens’s syndrome, Hashimoto’s thyroiditis, scleroderma, and CREST syndrome [8]. Similar to other liver diseases, portal hypertension and its complications often develop late in the course of PBC, when patients have well-established cirrhosis. Ursodeoxycholic acid (UDCA) dosed at 13–15 mg/kg/day is the only therapy for PBC approved by the U.S. Food and Drug Administration and the only one recommended by the practice guidelines of both the European and the American Associations for the Study of Liver Diseases for PBC patients with abnormal biochemical values [9, 10]. UDCA is an epimer of the primary human bile acid chenodeoxycholic acid (CDCA) and with a mechanism of action that is not clearly understood but is widely believed to enhance choleresis at different levels [11]. UDCA is believed to protect hepatocytes from toxic concentrations of other endogenous bile acids. UDCA also stimulates ductular and hepatocellular bile acids secretion by modulation of gene transcription and post-transcriptional events, leading to an up-regulation of the bile salt export pump (BSEP) and multidrug resistance-associated protein 2 (MRP2). An anti-apoptotic effect of UDCA has also been reported via stabilization of hepatocyte membranes and enhancement of defenses against oxidative stress [12]. It has also been reported as a key modulator of cell cycle regulation [13]. A number of randomized controlled studies have been conducted to evaluate UDCA efficacy in PBC. All studies have demonstrated a significant improvement in serum markers of cholestasis and biliary injury together with a consistent reduction of IgM and AMA titers [14–21]. In general, UDCA has been associated with a reduced risk of developing varices and slower histological progression [10]. Moreover, the survival rate of patients with stage 1 or 2 disease given UDCA long term was similar to that of a healthy control population [22]. Some meta-analyses have questioned the survival benefits of UDCA in PBC [23–25]. However, these meta-analyses have often included studies of short duration and studies utilizing low doses of UDCA. Moreover, great efforts over the last 10 years have been spent to define the response criteria to UDCA focusing on prognostic biomarkers and cross-validation of predicting values for the response of UDCA on transplant-free survival from PBC [26–29]. UDCA-responsive patients will generally show biochemical improvement within 6–9 months; however, those who do not achieve these benchmarks are at risk for progressive decline. In spite of its beneficial effects, UDCA remains ineffective in up to 40 % of patients, depending on sex and age at diagnosis
with male sex and a young age at diagnosis being independent predictors of UDCA non-response [30]. Although a wide variety of agents other than UDCA, including methotrexate, malotilate, silymarin, cyclosporine A, colchicine, thalidomide, and chlorambucil, have been studied in clinical trials for the treatment of PBC, the results have not been encouraging [31]. Herein, we review a number of novel therapies investigated in open-label and randomized clinical trials which may eventually lead to more effective treatments of PBC patients with incomplete responses to UDCA.
Budesonide Budesonide is a synthetic steroid with high first-pass metabolism in the liver limiting its systemic adverse effects compared to standard treatment with steroids (Table 1). First used in the treatment of inflammatory bowel diseases, budesonide (9 mg/day) was initially studied in a 2-year randomized trial as an add-on therapy to UDCA [32]. Compared to placebo, a significant improvement in liver function tests and liver histology was found in the group taking UDCA plus budesonide. Notably, no significant effects on bone density loss or adrenal suppression were identified. A subsequent 3-year open-label trial was performed in 77 patients with PBC (stages I to III) randomized into two arms: budesonide 6 mg/day plus UDCA 15 mg/kg/day and UDCA 15 mg/day as monotherapy [33]. In the combination group treated with UDCA and budesonide, liver fibrosis decreased by 25 % but increased 70 % in the group taking UDCA monotherapy. In contrast, an open-label, pilot study of 22 PBC patients with a suboptimal response to UDCA showed only a marginal improvement in alkaline phosphatase (ALP), but a significant increase in Mayo score prognostic index and a significant loss of bone mass [34]. Finally, budesonide (6 mg/day) in combination with UDCA and mycophenolate mofetil (1.5 mg/day) was studied in 15 patients with non-cirrhotic PBC and a suboptimal response to UDCA [35]. Patients also received calcium and vitamin D supplementation, and rifampicin for pruritus if necessary. Six out the 15 patients (41 %) experienced a complete normalization of biochemical tests with therapy, and seven show a partial biochemical response. Liver biopsy performed after 3 years of treatment showed a marked improvement in histological activity and fibrosis. Despite these promising findings, in late-stage liver disease budesonide is contraindicated due to the high risk of serious adverse events, particularly portal vein thrombosis [36]. In conclusion, budesonide in combination with UDCA may be effective in selected patients with a suboptimal response to UDCA. The results of a phase III placebo-controlled randomized double-blind study comparing UDCA plus budesonide against UDCA plus placebo are anticipated to resolve this issue (Eudra CT number 2007-004040-70).
Clinic Rev Allerg Immunol Table 1 Studies of primary biliary cirrhosis involving budesonide Author
Trial
Subjects (n)
Duration
Outcome
Leuschner [32]
DB, PBO UDCA+Bud vs. UDCA+placebo
20
2 years
Rautiainen [33]
77
3 years
Angulo [34]
Randomized UDCA+Bud vs. UDCA alone Pilot UDCA+Bud
22
Rabahi [35]
Pilot UDCA+Bud+MFM
15
A mean of 46 months 3 years
Significant improvement in LFTs in UDCA+Bud; improvement in liver histology Improvement in liver histology in the group of UDCA+Bud No additional benefit to UDCA 6/15 (41 %) experienced complete normalization of LFTs; improvement in liver histology
DB double blind, PBO placebo
Obeticholic Acid (OCA) 6a-Ethyl-chenodeoxycolic acid (6-ECDCA) or obeticholic acid (OCA), also known as INT-747, is a novel derivative of the primary human bile acid chenodeoxycholic acid (CDCA), a natural ligand for the farnesoid X receptor (FXR). FXR is a nuclear receptor involved in the regulation of hepatic bile acid production and also modulates hepatic inflammation, fibrosis, and regeneration. Notably, OCA is approximately 100 times more potent than CDCA in FXR activation [37]. Like UDCA, OCA increases bile flow in cholestatic conditions thus protecting the hepatocytes from toxic concentrations of other endogenous bile acids. In addition, both UDCA and OCA increase the presence of bile acid transport proteins, including the multidrug resistance-associated protein 2 (MRP2) and BSEP, on the canalicular membrane and have anti-apoptotic effects [38]. However, unlike UDCA which is a very weak FXR agonist, OCA shows transcription-related mechanisms via its potent FXR agonist properties. The resulting induction of the bile acid signaling pathway via fibroblast growth factor19 (FGF-19) likely explains the more potent hepatoprotective effects of OCA. OCA has also demonstrated potent antiinflammatory effects in animal models, and preclinical studies have shown that OCA can reverse fibrosis and decrease portal hypertension in both the thioacetamide and bile duct ligation models [39–41]. Two randomized phase II trials in patients with PBC treated with OCA for 3 months have been reported (Table 2). The primary endpoint of both trials was improvement in ALP levels. The first, 747–202 [42], evaluated UDCA plus on of three doses of OCA (10, 25, and 50 mg) versus UDCA plus placebo in patients who presented persistent elevations in ALP levels greater than 1.5 times the upper limit of normal (ULN) while on a stable dose of UDCA. Clinically significant reductions in ALP were observed with all three doses of OCA versus placebo with mean ALP reductions of approximately 20–25 % with OCA compared to 3 % with placebo.
Statistically significant improvements were also seen in γglutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and conjugated bilirubin levels. This phase was then followed by an open-label longterm safety extension (LTSE) phase. The second study evaluated OCA as monotherapy comparing the effects of 10 and 50 mg OCA versus placebo [43]. Statistically significant relative and absolute reductions in ALP with both doses of OCA versus placebo were reported as well as significant improvements in GGT, conjugated bilirubin, C-reactive protein, immunoglobulin M (IgM), and tumor necrosis factor-alpha (TNF-α). Pruritus was the only clear clinically meaningful adverse event that differed between OCA treatment and placebo in both of the studies. The severity of the pruritus and the incidence of discontinuations due to pruritus were dose related, being reported more in patients treated with higher doses in both studies. Interim results of the only phase III study of OCA, the PBC OCA International Study of Efficacy (POISE), have recently been presented [44]. The POISE trial is an international, multicenter, placebo-controlled, randomized clinical trial designed to study the safety and efficacy of once-daily OCA in PBC patients with an incomplete response to or unable to tolerate UDCA. The primary endpoint of the 12-month double-blind portion of the trial was the achievement of both an ALP level
New Therapies for Primary Biliary Cirrhosis Annarosa Floreani & Irene Franceschet & Lisa Perini & Nora Cazzagon & M. Eric Gershwin & Christopher L. Bowlus
# Springer Science+Business Media New York 2014
Abstract Primary biliary cirrhosis (PBC) is a rare inflammatory liver disease for which ursodeoxycholic acid (UDCA) is the only therapy approved by the U.S. Food and Drug Administration. Patients with a biochemical response to UDCA therapy have a similar survival rate compared to the general population. However, up to 40 % of PBC patients do not achieve a complete response to UDCA, have an increased risk of liver-related death and liver transplantation, and represent a persistent medical need for new therapies. Several novel drugs have recently been studied and show potential efficacy in PBC. Obeticholic acid, a farnesoid X receptor agonist, has been tested in phase II trials and initial results after 1 year in a phase III international trial suggest that it may be effective in achieving a biochemical response in approximately 40 % of patients who do not completely respond to UDCA. Several small studies on fibrates have suggested that they may have efficacy, but larger studies are needed. Surprisingly, results of immunomodulators and biologics have not yet been able to demonstrate efficacy, but new approaches have shown promise in animal models and their translation to human clinical trials are awaited.
A. Floreani (*) : I. Franceschet : L. Perini : N. Cazzagon Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy e-mail: [email protected] M. E. Gershwin Division of Rheumatology, Allergy, and Clinical Immunology, University of California Davis, Davis, CA, USA C. L. Bowlus Division of Gastroenterology and Hepatology, University of California Davis, Davis, CA, USA
Keywords Primary biliary cirrhosis . Ursodeoxycholic acid . Obeticholic acid . Anti-TNF-α . CXCL10 monoclonal antibody . Budesonide . Fibrates
Introduction Primary biliary cirrhosis (PBC) is a chronic liver disease characterized by progressive immune-mediated destruction of the small-to-medium-sized bile ducts, resulting in chronic cholestasis, portal inflammation, and fibrosis that can lead to cirrhosis and, ultimately, liver failure [1]. PBC is a complex disease whose etiology is not completely understood. It is now widely accepted that PBC results from an environmental stimulus intervening on a genetically susceptible background, causing the loss of tolerance to mitochondrial self-antigens, evidenced by the presence of anti-mitochondrial antibodies (AMA) in more than 80 % of cases, and an immune response against intrahepatic biliary epithelial cells [2]. The autoimmune pathogenesis of PBC is supported by its epidemiological characteristics; the presence of highly specific autoantibodies in the serums of patients; and an inflammatory CD4+ and CD8+ T-cells infiltrate against the same self-antigens. In addition to the classic AMA, anti-nuclear antibodies (ANAs) are present in approximately 50 % of patients with two particular fluoroscopic patterns: nuclear-rim (against the glycoprotein 210 and nuclearporin 62) and multiple nuclear-dots (against the Sp100 and PML proteins) [3]. Further, PBCspecific autoantibodies to Kelch-like 12 and hexokinase have also been described [4]. Initially described in women with advanced disease, i.e., cirrhosis, the moniker primary biliary cirrhosis has become a misnomer as the clinical presentation has changed over the years with the majority of patients having mild disease at diagnosis [5, 6]. In addition to the life-threatening complications of cirrhosis, quality of life related to PBC includes
Clinic Rev Allerg Immunol
fatigue and pruritus, although symptomatology is not correlated with disease activity or severity. However, the presence of fatigue and pruritus at diagnosis in recent studies appears to identify a subgroup of patients with a disease that is less responsive to UDCA treatment and more prone to progress to cirrhosis and liver failure [7]. The coexistence of other autoimmune disorders is common including Raynaud’s phenomenon, Sjogrens’s syndrome, Hashimoto’s thyroiditis, scleroderma, and CREST syndrome [8]. Similar to other liver diseases, portal hypertension and its complications often develop late in the course of PBC, when patients have well-established cirrhosis. Ursodeoxycholic acid (UDCA) dosed at 13–15 mg/kg/day is the only therapy for PBC approved by the U.S. Food and Drug Administration and the only one recommended by the practice guidelines of both the European and the American Associations for the Study of Liver Diseases for PBC patients with abnormal biochemical values [9, 10]. UDCA is an epimer of the primary human bile acid chenodeoxycholic acid (CDCA) and with a mechanism of action that is not clearly understood but is widely believed to enhance choleresis at different levels [11]. UDCA is believed to protect hepatocytes from toxic concentrations of other endogenous bile acids. UDCA also stimulates ductular and hepatocellular bile acids secretion by modulation of gene transcription and post-transcriptional events, leading to an up-regulation of the bile salt export pump (BSEP) and multidrug resistance-associated protein 2 (MRP2). An anti-apoptotic effect of UDCA has also been reported via stabilization of hepatocyte membranes and enhancement of defenses against oxidative stress [12]. It has also been reported as a key modulator of cell cycle regulation [13]. A number of randomized controlled studies have been conducted to evaluate UDCA efficacy in PBC. All studies have demonstrated a significant improvement in serum markers of cholestasis and biliary injury together with a consistent reduction of IgM and AMA titers [14–21]. In general, UDCA has been associated with a reduced risk of developing varices and slower histological progression [10]. Moreover, the survival rate of patients with stage 1 or 2 disease given UDCA long term was similar to that of a healthy control population [22]. Some meta-analyses have questioned the survival benefits of UDCA in PBC [23–25]. However, these meta-analyses have often included studies of short duration and studies utilizing low doses of UDCA. Moreover, great efforts over the last 10 years have been spent to define the response criteria to UDCA focusing on prognostic biomarkers and cross-validation of predicting values for the response of UDCA on transplant-free survival from PBC [26–29]. UDCA-responsive patients will generally show biochemical improvement within 6–9 months; however, those who do not achieve these benchmarks are at risk for progressive decline. In spite of its beneficial effects, UDCA remains ineffective in up to 40 % of patients, depending on sex and age at diagnosis
with male sex and a young age at diagnosis being independent predictors of UDCA non-response [30]. Although a wide variety of agents other than UDCA, including methotrexate, malotilate, silymarin, cyclosporine A, colchicine, thalidomide, and chlorambucil, have been studied in clinical trials for the treatment of PBC, the results have not been encouraging [31]. Herein, we review a number of novel therapies investigated in open-label and randomized clinical trials which may eventually lead to more effective treatments of PBC patients with incomplete responses to UDCA.
Budesonide Budesonide is a synthetic steroid with high first-pass metabolism in the liver limiting its systemic adverse effects compared to standard treatment with steroids (Table 1). First used in the treatment of inflammatory bowel diseases, budesonide (9 mg/day) was initially studied in a 2-year randomized trial as an add-on therapy to UDCA [32]. Compared to placebo, a significant improvement in liver function tests and liver histology was found in the group taking UDCA plus budesonide. Notably, no significant effects on bone density loss or adrenal suppression were identified. A subsequent 3-year open-label trial was performed in 77 patients with PBC (stages I to III) randomized into two arms: budesonide 6 mg/day plus UDCA 15 mg/kg/day and UDCA 15 mg/day as monotherapy [33]. In the combination group treated with UDCA and budesonide, liver fibrosis decreased by 25 % but increased 70 % in the group taking UDCA monotherapy. In contrast, an open-label, pilot study of 22 PBC patients with a suboptimal response to UDCA showed only a marginal improvement in alkaline phosphatase (ALP), but a significant increase in Mayo score prognostic index and a significant loss of bone mass [34]. Finally, budesonide (6 mg/day) in combination with UDCA and mycophenolate mofetil (1.5 mg/day) was studied in 15 patients with non-cirrhotic PBC and a suboptimal response to UDCA [35]. Patients also received calcium and vitamin D supplementation, and rifampicin for pruritus if necessary. Six out the 15 patients (41 %) experienced a complete normalization of biochemical tests with therapy, and seven show a partial biochemical response. Liver biopsy performed after 3 years of treatment showed a marked improvement in histological activity and fibrosis. Despite these promising findings, in late-stage liver disease budesonide is contraindicated due to the high risk of serious adverse events, particularly portal vein thrombosis [36]. In conclusion, budesonide in combination with UDCA may be effective in selected patients with a suboptimal response to UDCA. The results of a phase III placebo-controlled randomized double-blind study comparing UDCA plus budesonide against UDCA plus placebo are anticipated to resolve this issue (Eudra CT number 2007-004040-70).
Clinic Rev Allerg Immunol Table 1 Studies of primary biliary cirrhosis involving budesonide Author
Trial
Subjects (n)
Duration
Outcome
Leuschner [32]
DB, PBO UDCA+Bud vs. UDCA+placebo
20
2 years
Rautiainen [33]
77
3 years
Angulo [34]
Randomized UDCA+Bud vs. UDCA alone Pilot UDCA+Bud
22
Rabahi [35]
Pilot UDCA+Bud+MFM
15
A mean of 46 months 3 years
Significant improvement in LFTs in UDCA+Bud; improvement in liver histology Improvement in liver histology in the group of UDCA+Bud No additional benefit to UDCA 6/15 (41 %) experienced complete normalization of LFTs; improvement in liver histology
DB double blind, PBO placebo
Obeticholic Acid (OCA) 6a-Ethyl-chenodeoxycolic acid (6-ECDCA) or obeticholic acid (OCA), also known as INT-747, is a novel derivative of the primary human bile acid chenodeoxycholic acid (CDCA), a natural ligand for the farnesoid X receptor (FXR). FXR is a nuclear receptor involved in the regulation of hepatic bile acid production and also modulates hepatic inflammation, fibrosis, and regeneration. Notably, OCA is approximately 100 times more potent than CDCA in FXR activation [37]. Like UDCA, OCA increases bile flow in cholestatic conditions thus protecting the hepatocytes from toxic concentrations of other endogenous bile acids. In addition, both UDCA and OCA increase the presence of bile acid transport proteins, including the multidrug resistance-associated protein 2 (MRP2) and BSEP, on the canalicular membrane and have anti-apoptotic effects [38]. However, unlike UDCA which is a very weak FXR agonist, OCA shows transcription-related mechanisms via its potent FXR agonist properties. The resulting induction of the bile acid signaling pathway via fibroblast growth factor19 (FGF-19) likely explains the more potent hepatoprotective effects of OCA. OCA has also demonstrated potent antiinflammatory effects in animal models, and preclinical studies have shown that OCA can reverse fibrosis and decrease portal hypertension in both the thioacetamide and bile duct ligation models [39–41]. Two randomized phase II trials in patients with PBC treated with OCA for 3 months have been reported (Table 2). The primary endpoint of both trials was improvement in ALP levels. The first, 747–202 [42], evaluated UDCA plus on of three doses of OCA (10, 25, and 50 mg) versus UDCA plus placebo in patients who presented persistent elevations in ALP levels greater than 1.5 times the upper limit of normal (ULN) while on a stable dose of UDCA. Clinically significant reductions in ALP were observed with all three doses of OCA versus placebo with mean ALP reductions of approximately 20–25 % with OCA compared to 3 % with placebo.
Statistically significant improvements were also seen in γglutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and conjugated bilirubin levels. This phase was then followed by an open-label longterm safety extension (LTSE) phase. The second study evaluated OCA as monotherapy comparing the effects of 10 and 50 mg OCA versus placebo [43]. Statistically significant relative and absolute reductions in ALP with both doses of OCA versus placebo were reported as well as significant improvements in GGT, conjugated bilirubin, C-reactive protein, immunoglobulin M (IgM), and tumor necrosis factor-alpha (TNF-α). Pruritus was the only clear clinically meaningful adverse event that differed between OCA treatment and placebo in both of the studies. The severity of the pruritus and the incidence of discontinuations due to pruritus were dose related, being reported more in patients treated with higher doses in both studies. Interim results of the only phase III study of OCA, the PBC OCA International Study of Efficacy (POISE), have recently been presented [44]. The POISE trial is an international, multicenter, placebo-controlled, randomized clinical trial designed to study the safety and efficacy of once-daily OCA in PBC patients with an incomplete response to or unable to tolerate UDCA. The primary endpoint of the 12-month double-blind portion of the trial was the achievement of both an ALP level
