Obeticholsäure (1) – Ocaliva®

• Clinical trials
  • The results used for the benefit assessment were derived from the three-arm, randomised, multicentre, controlled POISE trial. In the double-blind phase of the trial, two dosing regimens (10 mg; titration from 5 mg to 10 mg) of OCA, each administered in addition to standard therapy with ursodeoxycholic acid (UDCA), were compared with placebo (Arm 1: 5 to a maximum of 10 mg, Arm 2: 10 mg throughout).

Treatment of primary biliary cholangitis (also known as primary biliary cirrhosis) in combination with ursodeoxycholic acid (UDCA) in adults who have an inadequate response to UDCA, or as monotherapy in adults who cannot tolerate UDCA

• Non-quantifiable
• Consequently, the G-BA classifies the extent of the additional benefit of obeticholic acid as non-quantifiable on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease. There is an additional benefit, but it is non-quantifiable because the scientific evidence does not permit this.
• mortality
  • Only one death occurred in the OCA group during the study. Due to the small number of cases, this result cannot be used as evidence of the benefits or harms of OCA.
  • Given the long course of primary biliary cholangitis (PBC), results on mortality sufficient to support a valid conclusion are only to be expected after a long period of observation.
  • In summary, no conclusions regarding the extent of the additional benefit can be drawn from the mortality results.
• morbidity
  • The primary endpoint of the POISE study, both in the 12-month DB phase and in the LTSE phase, comprises three individual components: the proportion of patients with alkaline phosphatase (ALP) < 1.67 × the upper limit of normal (ULN) and total bilirubin ≤ ULN, and an ALP reduction of ≥ 15 per cent. The laboratory parameters were classified as not relevant to patients for the purposes of this benefit assessment.
  • Symptoms perceptible to the patient are not taken into account, and no direct effects on the patient can be inferred.
  • Surrogate validation for the patient-relevant endpoints of mortality and liver transplantation is insufficient when derived exclusively from registry data.
  • Based on the limited data presented on patient-relevant endpoints, only the results on pruritus could be used to analyse the efficacy of OCA.
  • The results of the 12-month double-blind phase show that, for the symptom of pruritus in adults with PBC—whether assessed using the 5-D pruritus questionnaire or the visual analogue scale (VAS) pruritus – no statistically significant differences were observed between the two treatment arms, either in terms of the total score or the individual domains of the 5-D questionnaire.
  • Furthermore, the clinical relevance of these differences is unclear due to the absence of a ‘minimal important difference’ (MID) for a between-group difference.
  • In summary, no conclusions regarding the extent of the additional benefit can be drawn from the results on morbidity.
• quality of life
  • The PBC-40 questionnaire, comprising the domains of general symptoms, itching, fatigue, cognitive functioning, social functioning and emotional functioning, was used to assess quality of life.
  • During the 12-month double-blind phase, the PBC-40 questionnaire showed no statistically significant difference between the OCA titration group and the placebo group in any of the domains at month 6 or month 12.
  • Based on the results, it can only be concluded that quality of life in the individual domains was reported at rather low scores at baseline. This suggests a less impaired quality of life, which changed only marginally over the 12-month treatment period.
  • However, the clinical relevance of these differences is unclear due to the absence of a Minimum Imaginable Difference (MID) for a between-group difference.
  • In summary, no conclusions regarding the extent of the additional benefit can be drawn from the quality of life results.
• Side effects
  • The most common adverse event (AE) in the OCA titration group was pruritus. It occurred statistically significantly more frequently in the OCA group.
  • AE that led to discontinuation of study medication in the OCA titration group involved 5 patients (7 %), of whom one patient discontinued due to pruritus. This result is not statistically significant.
  • In the placebo group, 2 patients (3 %) discontinued the 12-month double-blind phase, but not due to pruritus.
  • As the AE pruritus frequently occurs as a symptom of the disease or is known to be a comorbidity, the overall assessment is difficult.
  • Overall, a statistically significant higher number of patients in the OCA titration group (22 patients [31 %]) experienced severe AEs than in the placebo group (9 patients [14 %]).
  • Pruritus was the most commonly reported severe AE (OCA titration: 13 patients [19%]; placebo: 5 patients [7%]), which is a statistically significant finding to the detriment of OCA.
  • A SAE was reported for 11 patients (16 %) in the OCA titration group, which was statistically significantly more frequent than in the placebo group (N = 3 (4 %)).
  • In the LTSE phase, changes in the incidence of adverse events due to OCA cannot be assessed due to the lack of parallel control groups.
• Overall assessment / Conclusion
  • Meaningful results for patient-relevant endpoints can only be expected after a long observation period due to the prolonged course of primary biliary cholangitis (PBC).
  • To assess the additional benefit, the arm of the double-blind study phase of the randomised controlled POISE trial, in which patients were treated in accordance with the marketing authorisation, was used; in this phase, two doses of OCA were compared with placebo, each in addition to baseline therapy with ursodeoxycholic acid (UDCA), were compared.
  • No significant differences were observed for patient-relevant endpoints in the categories of mortality, morbidity or quality of life.
  • With regard to side effects, significant differences were observed to the detriment of OCA in the endpoint categories of severe AEs, SAEs and pruritus.
  • Assessing the differences in the AE ‘pruritus’ to the detriment of OCA is complicated by the fact that it frequently occurs as a symptom of the disease or is known to be a comorbidity.
  • For the laboratory parameters ALP and bilirubin concentration, a difference was observed in favour of obeticholic acid; however, these endpoints have not been validated in relation to patient-relevant endpoints.
  • Given the short study duration of 1 year and the chronic nature of the disease, no results regarding patient-relevant endpoints such as mortality or quality of life can be expected; these can only be assessed over a longer follow-up period.

Courtesy translation only, please refer to the German original.