Avacopan (1) – Tavneos®

• Clinical trials
  • The ADVOCATE trial was a randomised, double-blind, multicentre, controlled trial comparing the efficacy and safety of avacopan with prednisone, each in combination with background therapy.
  • In addition, the pharmaceutical manufacturer has submitted the CLEAR study (CL002_168). This is a randomised, double-blind, placebo-controlled, three-stage Phase II trial with a treatment duration of 12 weeks, designed to investigate the safety and efficacy of avacopan in adults with GPA, MPA or renal-limited vasculitis.

Adults with severe active granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA)

• For adults with severe active granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA), there is a hint of a minor additional benefit for avacopan in combination with a rituximab or cyclophosphamide dosage regimen.
• Overall, there is a hint of a minor additional benefit of avacopan in combination with a rituximab or cyclophosphamide dosage regimen.
• mortality
  • No endpoint was evaluated in the ‘mortality’ category. Deaths were recorded as part of the safety monitoring. By the end of the study, there had been 2 (1 %) deaths in the avacopan arm and 4 (2 %) deaths in the prednisone arm.
• Morbidity – Remission and sustained remission
  • Both remission and the maintenance of remission are key therapeutic objectives in this therapeutic indication and are of high clinical relevance.
  • In the avacopan arm, 72% of patients achieved remission at week 26, compared with 70% in the prednisone arm. No statistically significant difference was observed between the study arms for the ‘remission’ endpoint.
  • ‘Sustained remission’ was achieved by 66% of patients in the avacopan arm and 55% in the prednisone arm. Based on the stratified one-sided p-value, a statistically significant advantage was observed for this endpoint in favour of avacopan compared with prednisone.
• Morbidity – Health Status (EQ-5D VAS)
  • Health status was assessed in the ADVOCATE study using the visual analogue scale of the European Quality of Life – 5 Dimensions (EQ-5D-VAS). At week 26, there was no statistically significant difference between the treatment arms. At week 52, however, there was a statistically significant advantage for avacopan compared with prednisone. The 95% confidence interval (CI) for the standardised mean difference (SMD), expressed as Hedges’ g, does not lie entirely outside the non-significant range of –0.2 to 0.2; consequently, the clinical relevance of this effect cannot be assessed.
• quality of life
  • In the ADVOCATE trial, health-related quality of life was assessed using the total score of the Short Form-36 Health Survey (SF-36).
  • Whilst no statistically significant difference between the study arms was observed for the mental health subscale (MCS) at either week 26 or week 52, a statistically significant difference in favour of avacopan was observed for the physical health subscale (PCS), a statistically significant advantage in favour of avacopan was observed at both week 26 and week 52. However, the 95% CI of the SMD, expressed as Hedges’ g, does not lie entirely outside the irrelevance range of –0.2 to 0.2, meaning that the clinical relevance of this effect cannot be assessed.
• Side effects
  • For the analysis of endpoints in the ‘side effects’ category, adverse events (AEs) that occurred from the first dose of the study medication on Day 1 up to Week 60 – i.e. including the 8-week follow-up after the end of treatment – were taken into account.
  • No statistically significant differences were observed between the treatment arms in the overall rates of serious AEs and AEs leading to discontinuation of the study medication.
  • For AEs, a statistically significant advantage in favour of avacopan compared with prednisone was observed at the level of the MedDRA System Organ Classes (SOC) and Preferred Terms (PT) for the SOCs ‘Eye diseases’, ‘Benign, malignant and unspecified neoplasms (including cysts and polyps)’ and ‘Endocrine disorders’.
  • Overall, the results in the ‘Side Effects’ category are subject to uncertainty, as the pharmaceutical manufacturer has not provided any analyses in which events relating to the underlying disease (captured via the PT ‘Anti-neutrophil cytoplasmic antibody-positive vasculitis’) were excluded from the overall rates of AEs, severe AEs (grade ≥ 3), SAEs and discontinuations due to AEs.
• Overall assessment / Conclusion
  • In the mortality endpoint category, neither an advantage nor a disadvantage was observed.
  • In the morbidity category, there was a statistically significant advantage in favour of avacopan for the patient-relevant endpoint ‘sustained remission’, whilst no advantages or disadvantages were observed for the endpoint ‘remission’. For the endpoint ‘health status’, a statistically significant advantage in favour of Avacopan was observed at week 52; however, the clinical relevance of this effect cannot be assessed.
  • For health-related quality of life, as assessed using the SF-36, no statistically significant difference was observed between Avacopan and prednisone for the mental health summary score. A statistically significant advantage was observed for the physical summary score at weeks 26 and 52; however, the clinical relevance of this finding cannot be assessed.
  • With regard to side effects, no advantage or disadvantage of Avacopan compared with prednisone was identified, in each case when used in combination with a cyclophosphamide or rituximab treatment regimen. In detail, for AEs at the SOC and PT levels, a statistically significant advantage in favour of Avacopan compared with prednisone was observed for ‘eye diseases’, ‘benign, malignant and unspecified neoplasms (including cysts and polyps)’ and ‘endocrine disorders’.
  • Taking the available results as a whole, an additional benefit can be inferred for Avacopan based on the statistically significant advantage in the morbidity endpoint ‘sustained remission’, the extent of which is assessed as minor.
• Validity of the evidence
  • For the ADVOCATE randomised controlled trial, on which this benefit assessment is based, the potential for bias at the study level is assessed as low.
  • Uncertainties arise primarily due to the lack of maintenance therapy following initial treatment with rituximab, contrary to current guideline recommendations.
  • In order to assess the sustainability of the effects, in particular the maintenance of remission, a longer study duration would also have been necessary, taking into account the opinions of clinical experts and the findings of the EMA’s Public Assessment Report (EPAR).
  • Overall, the uncertainties mentioned regarding the validity of the evidence provide a hint of additional benefit.

Courtesy translation only, please refer to the German original.