4 responses to “New treatment option for Primary Biliary Cholangitis (PBC)”

  1. 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.

  2. 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.

  3. 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.

    Hin Hin, Ed and Shirely

  4. Thank you for this interesting and informative response.

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