By Shirley Jiang MD (biography, no disclosures), Edward Tam MD FRCPC (biography and disclosures), and Hin Hin Ko MD FRCPC (biography and disclosures)
Disclosures and mitigating statements:
Dr. Tam: Disclosures: Intercept Pharmaceuticals: Advisory board/speaker honoraria/clinical investigator. Mitigating potential bias: Recommendations are consistent with current practice patterns and published guidelines (Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases).
Dr. Ko: Disclosures: Intercept Pharmaceuticals: Advisory board/speaker honoraria/clinical investigator. Mitigating potential bias: Recommendations are consistent with current practice patterns and published guidelines (Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases).
What I did before
Primary biliary cholangitis (PBC) is the most common autoimmune liver disease with an incidence of 1 in 1000 in women over age 40.1 Histologically, it is characterized by progressive destruction of small and medium intrahepatic bile ducts. While some patients will have pruritus and fatigue, up to 50% of patients are asymptomatic at presentation with elevated cholestatic liver enzymes (i.e. alkaline phosphatase (ALP) and gamma glutamyl transferase (GGT)). Without treatment, PBC can progress towards liver fibrosis, cirrhosis, need for transplantation, and death. Disease progression can be monitored by surrogate biochemical markers, specifically ALP and total bilirubin, whereby lower levels are predictive of improved transplant-free survival.2
For decades, the only evidence-based treatment was ursodeoxycholic acid (UDCA), a naturally occurring bile acid. Multiple studies have shown that UDCA can improve liver biochemistry, delay progression of liver disease, and prolong transplant-free survival.3 Unfortunately, the rate of inadequate response to UDCA, defined by lack of improvement in biochemical markers, is up to 40% depending on the population. Inadequate UDCA response is more common in younger patients, males, and is associated with a worse prognosis.4
Given a lack of other evidence-based options to escalate treatment beyond UDCA monotherapy, it was previously common for PBC patients to have minimal biochemical monitoring once on UDCA, despite strong evidence that survival is correlated with normalization of ALP and bilirubin.
What changed my practice
In May 2017, Health Canada approved the use of obeticholic acid (OCA) for the treatment of PBC. OCA is a synthetically modified bile acid and potent agonist of the farnesoid X nuclear receptor (FXR). It protects hepatocytes against bile acid toxicity by impairing bile acid synthesis, promoting choleresis, and regulating anti-inflammatory pathways.
The deciding trial was the POISE study, a phase 3 randomized controlled trial of OCA in PBC patients who had either an inadequate response to, or who were intolerant of, UDCA. The majority of patients enrolled (93%) were incomplete responders to UDCA and continued taking UDCA in combination with either placebo or OCA. Treatment with OCA was associated with a statistically significant improvement in ALP to <1.67x ULN (approximately 200 IU/L) and normalization of bilirubin after 1 year compared to the placebo group. This primary composite endpoint was achieved in 46% of OCA patients compared to 10% of placebo patients, with a number needed to treat of 2.78. Pruritus was the most common side effect of OCA, with higher incidence at a higher dose of 10mg at 68%, compared to 38% in the placebo group.5
Multiple other clinical studies have also found biochemical response with OCA in UCDA non-responders, both in placebo-controlled trial and real-world settings.6,7 OCA monotherapy has also been demonstrated to improve ALP levels compared to placebo in a randomized clinical trial.8 Emerging interim data from the open-label extension of the POISE trial after 3 years of OCA treatment has shown sustained reduction in ALP and bilirubin, compared to baseline levels.9
While biochemical response is a validated surrogate for transplant-free survival, study of harder endpoints is ongoing, particularly as these outcomes evolve over many years in the natural history of PBC. A subset of POISE participants (n=17) who underwent liver biopsy had histologic stabilization or improvement after 3 years of OCA treatment.10 The Phase 4 Study of Obeticholic Acid Evaluating Clinical Outcomes in Patients With Primary Biliary Cholangitis (COBALT) trial will be studying survival, transplant-free survival, and liver-associated complications, but remains in the recruitment phase.11
What I do now
UDCA remains first-line therapy for PBC with a long record of use and generic preparations but in non-responders, OCA treatment should be considered.
1) Patients treated with UDCA should have biochemical monitoring every 3-6 months.
Upon diagnosis of PBC, first-line treatment should be initiated with UDCA 13-15mg/kg/day, in two divided doses. Laboratory measures including ALP, GGT, AST, ALT, platelets, and total bilirubin should be obtained every 3-6 months. Depending on duration of treatment, biochemical response to UDCA should be determined with established criteria such as the Toronto criteria:12ALP <1.67x ULN (approximately 200 IU/L) after 2 years of UDCA treatment.
If these criteria are not met, specifically if ALP remains elevated over 200 IU/L despite UDCA treatment, it is prudent to first consider patient adherence, concomitant liver disease, and co-administration with bile acid sequestrants, which can decrease absorption of UDCA. If there is no other cause identified, a diagnosis of inadequate response to UDCA can be made.13
2) OCA should be used in combination with UDCA in patients with inadequate UDCA response.
UDCA should be continued as studies have suggested survival benefit, even in those with inadequate biochemical response.14 Only patients who are intolerant to UDCA should be treated with OCA alone.13
3) OCA dosing is based on the existing degree of liver impairment.
For patients who do not have cirrhosis or have Child-Pugh A cirrhosis, OCA can be started at 5mg/day for the first 3 months. If ALP remains elevated after 6 months and the patient is tolerating OCA, the dose can be increased to 10mg daily. Child-Pugh class should be re-calculated prior to escalating the dose.
Treatment in patients with moderate to severe liver impairment is not well established as there is a risk of dose-dependent hepatotoxicity in these populations; treatment should be initiated and monitored by a hepatologist.6,13 Patients with Child-Pugh B or C cirrhosis should be carefully evaluated under specialist care before consideration of OCA use.
4) Treatment with OCA can worsen pruritus.
The main side effect limiting OCA adherence is pruritus, which is also a prominent feature of PBC itself. Typically, if encountered, pruritis is noted within the first month of OCA initiation and decreases in severity over time with continued dosing. This can be addressed by lowering the dose of OCA with slow up-titration thereafter and/or initiation of bile acid sequestrants, such as cholestyramine. In some cases, temporary pause of OCA therapy, with subsequent re-introduction after adequate control of pruritis, may be an effective strategy to reach target dosing.
5) OCA is more costly than UDCA but has Limited Coverage through PharmaCare in British Columbia.
OCA (Oclavia) is covered by Special Authority in British Columbia as long as it is prescribed by a gastroenterologist to a patient not tolerating or not responding to UCDA (after an adequate trial of 12 months).15 The daily cost of OCA is $109.67 per 5mg or 10mg tablet, compared to UDCA cost of approximately $1.56 for 1000mg (typical dose for a 70kg patient).
References
- Hirschfield GM. Diagnosis of primary biliary cirrhosis. Best Pract Res Clin Gastroenterol. 2011;25(6):701-712. DOI: 10.1016/j.bpg.2011.10.005. (View with CPSBC or view with UBC)
- Lammers WJ, van Buuren HR, Hirschfield GM, et al. Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study. Gastroenterol. 2014;147(6):1338-1349.e5; quiz e15. DOI:10.1053/j.gastro.2014.08.029. (View with UBC or request with CPSBC)
- Floreani A, Caroli D, Variola A, et al. A 35-year follow-up of a large cohort of patients with primary biliary cirrhosis seen at a single centre. Liver Int. 2011;31(3):361-368. DOI:10.1111/j.1478-3231.2010.02366.x (View with CPSBC or view with UBC)
- Carbone M, Mells GF, Pells G, et al. Sex and age are determinants of the clinical phenotype of primary biliary cirrhosis and response to ursodeoxycholic acid. Gastroenterol. 2013;144(3):560-569.e7. DOI: 10.1053/j.gastro.2012.12.005. (View with UBC or request with CPSBC)
- Nevens F, Andreone P, Mazzella G, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med. 2016;375(7):631-643. DOI: 10.1056/NEJMoa1509840. (View with UBC or request with CPSBC)
- Hirschfield GM, Mason A, Luketic V, et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterol. 2015;148(4):751-761.e8. DOI: 10.1053/j.gastro.2014.12.005. (View)
- Roberts SB, Ismail M, Kanagalingam G, et al. Real-world effectiveness of obeticholic acid in patients with primary biliary cholangitis. Hepatol Commun. 2020;4(9):1332-1345. DOI: 10.1002/hep4.1518. (View)
- Kowdley KV, Luketic V, Chapman R, et al. A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis. Hepatol. 2018;67(5):1890-1902. DOI: 10.1002/hep.29569. (View)
- Trauner M, Nevens F, Shiffman ML, et al. Long-term efficacy and safety of obeticholic acid for patients with primary biliary cholangitis: 3-year results of an international open-label extension study. Lancet Gastroenterol Hepatol. 2019;4(6):445-453. DOI: 10.1016/S2468-1253(19)30094-9. (View)
- Bowlus CL, Pockros PJ, Kremer AE, et al. Long-term obeticholic acid therapy improves histological endpoints in patients with primary biliary cholangitis. Clin Gastroenterol Hepatol. 2020;18(5):1170-1178.e6. DOI: 10.1016/j.cgh.2019.09.050. (View with UBC or request with CPSBC)
- Harb G. Phase 4 Study of Obeticholic Acid Evaluating Clinical Outcomes in Patients With Primary Biliary Cholangitis (COBALT). Published May 20, 2021. Accessed July 13, 2021. (View)
- Kumagi T, Guindi M, Fischer SE, et al. Baseline ductopenia and treatment response predict long-term histological progression in primary biliary cirrhosis. Am J Gastroenterol. 2010;105(10):2186-2194. DOI: 10.1038/ajg.2010.216. (View with CPSBC or view with UBC)
- Lindor KD, Bowlus CL, Boyer J, Levy C, Mayo M. Primary biliary cholangitis: 2018 practice guidance from the American Association for the Study of Liver Diseases. Hepatol. 2019;69(1):394-419. DOI: 10.1002/hep.30145. (View)
- Harms MH, van Buuren HR, Corpechot C, et al. Ursodeoxycholic acid therapy and liver transplant-free survival in patients with primary biliary cholangitis. J Hepatol. 2019;71(2):357-365. DOI: 10.1016/j.jhep.2019.04.001. (View with CPSBC or view with UBC)
- Limited coverage drugs – obeticholic acid. PharmaCare. Accessed July 13, 2021. (View)
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That’s phenomenal! A new and more effective treatment for PBC was really needed. I have seen too many patients die from this condition over the years.
But you’re right, compliance is critical for survival.
However, I did not see mention of the importance of sobriety, a critical factor in any liver disease.
These patients need counselling and peer support.
I was curious about this treatment, so I looked up the POISE trial in NEJM. This shows changes in a composite surrogate outcome, but claims no clinical benefit. Indeed, serious adverse events were increased at both doses of obeticholic acid, vs. placebo. The lack of proof of clinical benefit (but not the evidence of increased harms) is discussed in the editorial, and the relevance of surrogate outcomes challenged in an Indian letter to NEJM correspondence. The NEJM editorial does refer to a “Phase 3b” ongoing study attempting to assess clinical outcomes. Is any information available from this? Did the authors search clinical trial registries since to see whether the “Phase 3b” study has produced any results, or how it is designed? Or is this the “Phase 4” (non-experimental) study referrred to as reference 11.
I would be interested to know how the authors of the TCMP article interpret the above issues.
Currently, there is an ongoing Phase 4 doble-blind, randomized, placebo-controlled, multicenter study (COBALT) undertaken at up to 170 sites internationally evaluating the effect of OCA on clinical outcomes in PBC. The duration of the study is expected to be 10 years (expected completion date is Dec 2024) and each subject is expected to have a minimum followup time of approximately 6 years (rough number they aim to recruit is about 400 patients). Based on the available information, patients who do not respond to Ursodiol are eligible and randomized to receive OCA 5mg (increase to 10mg) vs placebo. They are looking at multiple primary endpoints (survival, liver-associated complications, etc) by no interim reults are available yet. We reached out to Intercept and they are conducting outcomes-focused research that compares patients in the POISE (phase 3) Long-term safety extension to propensity score matched PBC patients from registries and they are hoping to present the results later this year.
After the POISE study, there are some results published from the post-hoc analysis of this trial and there is some real world-data published or presented at conferences. Below are a few references (#2 has already been included in the article).
1) For those patients with high baseline direct bilirubin levels >5.47umol/L (predictive of survival in PBC), there was a significant reduction in both direct and total bilirubin at month 12 compared with placebo. Mean change from baseline in direct bili at 12 mo was 4.17 umol/L for placebo, -3.28 umol/L for OCA 5mg and -3.66 umol/L for 10mg. Mean change in total bili at 12 mo were 4.38 umol/L for placebo, -4.53 for OCA 5-10mg and -5.06 umol/L for OCA 10mg. Reference: Pares A, et al. Liver Int. 2020; 40(5): 1121-1129.
2) A liver biopsy substudy for POISE. Small number of patients – 17 had liver biopsy at enrollment and after 3 yr of OCA. 71% had improvements or stabilization in fibrosis. There were significant reductions in collagen area ratio, fiber density and fibrosis composite score. Reference: Bowlus CL, et al. Clin Gastroenterol Hepatol. 2020; 18(5): 1170-1178.
3) A Canadian retrospective cohort study of patients with PBC with an incomplete response or intolerance to UDCA treated with OCA. There was a reduction in biochemical markers of cholestasis independent of whether patients met POISE trial inclusion trial. Rates of pruritus were similar. Treatment discontinuation was a bit higher at 17%. Reference: Roberts S, et al. Hepatology Communications. 2020; 4 (9): 1332-1345.
We recognize the need to generate data demonstrating improvement in hard clinical outcomes with respect to the use of obeticholic acid in PBC. As hard clinical outcomes such as death, hepatic decompensation, and need for liver transplant take many years to evolve in the natural history of PBC, this presents a challenge with determining the best timing as it relates to study design and regulatory approval of these medications such that patients may benefit as soon as possible from potentially beneficial therapy, while still recognizing the need to have sufficient safety and efficacy data for driving such approval. In the therapeutic space of PBC, clinicians and regulatory bodies have therefore become comfortable with the use of well-validated surrogate endpoints, and while not a replacement for clinical outcomes, it is important still to recognize that surrogate endpoints in PBC are in fact well-validated with respect to their relationship with clinical outcomes of interest.
Thanks,
Hin Hin, Ed and Shirely
Thank you for this interesting and informative response.