PBC treatment: the present and future Maggie Bassendine Professor of Hepatology
Primary biliary cirrhosis 20-25yrs OLT/ Death Symptoms: Fatigue, itching, jaundice Autoimmune disease: Focal small bile duct damage Autoreactivity: Antimitochondrial &/or antinuclear antibodies Autoreactivity preceeds clinical disease Environmental factors Polymorphic genes Refs: Mitchison HC et al. Hepatology 1986;6:1279-84, Metcalf J et al. Lancet 1996;384:1399-402
PBC treatment: the present Specific therapy- Ursodeoxycholic acid (UDCA) Treatment of symptoms Liver transplantation
Ursodeoxycholic acid (UDCA) China was the first country utilizing bear bile in traditional medicinal products (Tang Dynasty, 659 A.D). UDCA was found to be the primary bile acid produced in the liver of bears, compared to 3% of bile acid pool in humans. Japanese scientists succeeded in chemically synthesizing UDCA in 1955 UDCA is well tolerated After oral administration it undergoes an enterohepatic circulation and, in a dose of 13-15mg/kg/day, it becomes the predominant bile acid in human serum and bile.
Ursodeoxycholic acid (UDCA) UDCA is the only FDA drug licensed to treat patients with PBC. UDCA is recommended by the practice guidelines of both the European and the American Associations for the Study of Liver Diseases for PBC patients with abnormal liver biochemical values The dose of UDCA is important 13 to15 mg/kg/day Long-term treatment with UDCA can improve liver biochemistry and survival free of liver transplantation EASL Clinical Practice Guidelines: Management of cholestatic liver diseases J Hepatol 2009;51:237-67
Ursodeoxycholic acid (UDCA) UDCA responders UDCA non-responders Patients with a decrease in alkaline phosphatase of 40% or a decrease to normal at one year have a prognosis similar to that of an age-matched healthy population Absence of a biochemical response to UDCA has prognostic implications Adjuvant therapy may be considered in UDCA non-responders (± 40%) Ref: Pares A et al. Gastro 2006;130:715-20
Primary biliary cirrhosis
Primary biliary cirrhosis: disease progression In PBC the slowly progressive destruction of small bile ducts is accompanied by an increase in liver fibrosis, leading to biliary cirrhosis over a period of 10-25 years UDCA may be more effective when initiated at the earlier stages of disease Ref: Poupon R. J Hepatol.2010;52:745-758
PBC treatment: the present Treatment of symptoms: Pruritus: Cholestyramine, Rifampicin, Naltrexone Fatigue: Multifactorial etiology Modafinil can be tried EASL Clinical Practice Guidelines: Management of cholestatic liver diseases J Hepatol 2009;51:237-67 Liver transplantation: The only effective treatment for those with end-stage disease The model for end-stage liver disease (MELD) formula can be used to predict short-term survival a MELD score > 16 indicates a survival benefit from transplantation PBC patients should be considered by a transplant centre when the serum bilirubin level approaches 100mmol/l (6mg/100ml)
Definition of biochemical response to treatment with UDCA Angulo et al. (1999) ALP < 2 times ULN Pares et al (2006) ALP < 40% from baseline or to normal value Corpechot et al. (2008) ALP < 3 times ULN, AST < 2 times ULN, Bilirubin < 1.0 mg/dl Kuiper et al. (2009) Normal bilirubin and albumin (if one or both were abnormal before treatment); Normal bilirubin or albumin (if both were abnormal before treatment) Therapeutic trials with a new agent should target patients with incomplete biochemical response after 3-6 months of treatment with an adequate dose of UDCA. Complete biochemical response should be defined as ALP < 3 times ULN, AST < 2 times ULN, and bilirubin < 1.0 mg/dl (Corpechot et al. 2008) All therapeutic trials should compare UDCA with or without the new therapy. AASLD endpoints conference: Design and endpoints for clinical trials in primary biliary cirrhosis Silveira MG et al. Hepatology 2010;52:349-59
AASLD endpoints conference: Design and endpoints for clinical trials in primary biliary cirrhosis PBC affects fewer than 200,000 people in the United States and has been designated by the FDA as an orphan disease. If new therapeutic trials are targeted toward patients who are incomplete biochemical responders to UDCA, then the pool of potential study subjects drops to less than 40,000 nationwide. It is unavoidable that future clinical trials will require the collaboration of a large number of centres. A consortium of centres focused upon the study of PBC, including expertise in pathology, genetics, biliary physiology, immunology, biostatistics, and liver transplantation is urgently needed to spearhead and drive clinical trials of high quality. Silveira MG et al. Hepatology 2010;52:349-59
PBC treatment: the future Multicentre controlled trials comparing UDCA with combination therapy UDCA + immunosuppression [Budesonide] UDCA + FXR agonist UDCA + PPAR agonist New therapeutic targets eg IL12 pathway
Budesonide combined with UDCA: A 3 year prospective randomised trial PBC patients (n = 77, histological stage I-III), were randomised to Budesonide 6 mg/d + UDCA 15 mg/kg/d (n = 41) or UDCA monotherapy (n = 36) Histological stage improved in 22% of combination therapy but deteriorated in 20% of UDCA monotherapy Fibrosis decreased in 25% of combination therapy but increased in 70% of UDCA monotherapy Alkaline Phosphatase decreased in both arms Bilirubin rose in UDCA monotherapy arm but was stable in combination therapy (p = 0.002) Ref: Rautianen H et al. Hepatology 2005;41:747
Farnesoid-X X Receptor Agonists: a New Class of Drugs for the Treatment of PBC? An International Study Evaluating the Addition of INT-747 (Obeticholic Acid) to Ursodeoxycholic Acid Andrew Mason, Velimir Luketic, Keith Lindor, Gideon Hirschfield, Stuart Gordon, Marlyn Mayo, Kris Kowdley, Albert Parés, Michael Trauner, Erin Castelloe, Cathi Sciacca, Tessa Beecher Jones, Mark Pruzanski, David Shapiro and the INT-747 PBC Investigator Group U. Alberta, Virginia Commonwealth U., Mayo Clinic, U. Toronto, Henry Ford Clinic, U. Texas SW, Virginia Mason Med Center, U. Barcelona, U. Graz, Intercept Pharmaceuticals. EASL 2010
INT-747: 6α-Ethyl 6 Chenodeoxycholic Acid ( Obeticholic Acid) INT 747 6α ethyl chenodeoxycholic acid CDCA chenodeoxycholic acid UDCA ursodeoxycholic acid FXR EC 50 (agonist) 0.099 µm 8.66 µm No activity ~ 2 log FXR agonism Pelliciari R. J.Med.Chem 2002
INT-747: Addition to UDCA Dose Response Study Design UDCA N=35/group Placebo INT-747 10 mg Baseline Follow-Up INT-747 25 mg INT-747 50 mg Screening 0 2 4 8 12 14 Baseline 1-4 weeks predose Double Blind Phase 12 weeks Follow-Up Phase 2 weeks
INT-747: Addition to UDCA 8 Countries, 33 Centers (USA: 56%, Canada: 26%, Europe: 18%)
INT-747: Addition to UDCA Alkaline Phosphatase % 0 Day 15 29 57 85 Follow up % 10 20 Placebo (n=37) 10 mg (n=37) 25 mg (n=42) 50 mg (n=25) 30 Day 85 p<0.0001 all doses 40
INT-747: Addition to UDCA Principal AE = pruritus % Pruritus Severity 100 80 60 Mild Moderate Severe 30 20 Discontinuations Placebo 10mg 25mg 50mg 40 % 20 10 0 Placebo 10mg 25mg 50mg 0 Placebo 10mg 25mg 50mg Overall 10mg good efficacy & acceptably tolerated Phase 3 studies
Use of PPAR agonists (fibrates) in PBC Fukuo Y et al Nippon Ika Daigola Zasshi 1996;63:424 Iwasaki S et al Hepatol Res 1999;16:12 Miyaguchi S et al. Hepato-Gastoenterol. 2000;47:1518 Nakai S et al. Am J Gastro. 2000;95:326, Ohmoto K et al. Liver 2001;21:223 Kurihara T et al. Am J Gastro 2002;97:212 Yano K et al. Am J Gastro. 2002;97:41 Bezafibrate or Fenofibrate have been reported to be added to UDCA non-responders in >95 PBC patients with significant decrease in serum Alkaline Phosphatase levels Kanda T et al. J Gastroenterol. 2003;38:573 Itakura J et al. Hepatol Res. 2004 ;29:216 Dohmen K et al. WJG 2004;10:894 Akbar SM et al J Gastroenterol. 2005;40:157 Nakamuta M et al. J Gastroenterol 2005;40:546 Ohmoto K et al. J Gastroenterol. 2006;41:502 Iwasaki S et al. Hepatol Res. 2008;38:557 Walker LJ et al. Hepatology 2009;49:337-338 Hassan R et al. J Clin Gastroenterol 2010;44:371 Ref: Ohira H et al AJG 2002 2147
Adjuvant therapy in PBC: Effects of adding Fenofibrate in UDCA non-responders Fenofibrate (134-200mg daily) was added to UDCA in 16 patients with lack of biochemical response These PBC patients showed significant falls in ALP (p=0.0016) (89% falling to within the normal range) and IgM (p=0.0015) Ref: Walker LJ et al. Hepatology 2009;49:337-338
Genome-wide association studies in PBC In the combined Canadian and Italian data, IL12A and IL12RB2 were the strongest non- HLA associations. In the mouse model of PBC, signalling by way of IL-12p40 is an essential requirement for the development of autoimmune cholangitis The findings suggest involvement of the IL12 signalling pathways in the pathogenesis of PBC Refs: Liu X et al. Nature Genetics 2010;42:658, Yoshida K et al. Hepatology 2009;50:1347
IL12 signalling pathway (type-1 cytokine/receptor interactions) relevant for immunity against intracellular bacteria Manipulation of the IL12/IFNγ pathway may enable PBC to be cured in future Ref: Lamas DA et al. Int. J of Exp. Pathol. 2002,83:1-20
PBC treatment: the present and future