Dupilumab (1) – Dupixent®

• Clinical trials
  • The CHRONOS study (n=740) presented here is a randomised, double-blind, controlled, multicentre Phase 3 trial in which dupilumab in combination with topical glucocorticoids (TCS) is compared with placebo in combination with TCS.
  • In the dossier, the pharmaceutical manufacturer also cites the CAFE study to demonstrate additional benefit. The CAFE study is a randomised, double-blind Phase 3 study in which dupilumab is compared with placebo.

a) Treatment of moderate to severe atopic dermatitis (AD) in adult patients who are eligible for systemic therapy

• For the treatment of moderate to severe atopic dermatitis (AD) in adult patients who are eligible for systemic therapy, there is an indication for a considerable additional benefit of dupilumab compared with the appropriate comparator therapy.
• Overall, therefore, an indication is derived for the certainty of the conclusion.
• mortality
  • No deaths occurred in either of the relevant study arms up to week 52.
• Morbidity – pruritus (peak pruritus NRS)
  • An improvement of ≥ 4 points by week 52 is considered. For the pruritus endpoint, a statistically significant difference in favour of dupilumab compared with the appropriate comparator therapy was observed in the relevant patient population of the CHRONOS study. In the dupilumab arm, 69.7% of patients showed an improvement in pruritus; in the control arm, however, 36.9% of patients showed an improvement (relative risk (RR) 1.89; 95% confidence interval (CI) [1.50; 2.39]; p < 0.0001).
  • The results of the sensitivity analysis also show a statistically significant difference in favour of dupilumab in terms of achieving an improvement in pruritus (RR: 1.64; 95% CI [1.27; 2.12]).
• Morbidity – Eczema Area and Severity Index (EASI 75 and EASI 90 response)
  • An EASI 75 or EASI 90 response is considered clinically relevant. A statistically significant difference in favour of dupilumab was observed for both response thresholds (EASI 75 and EASI 90) (EASI 75: RR 1.52; 95% CI [1.28; 1.81]; p < 0.001; EASI 90: RR 2.03; 95% CI [1.56; 2.63]; p < 0.001).
  • Among patients treated with dupilumab, 73% achieved an EASI 75 response at week 52, whereas only 47.9% of patients treated with placebo plus TCS achieved EASI 75. At week 52, 56.6% of patients in the relevant dupilumab arm and 27.9% of patients in the placebo+TCS arm achieved an EASI 90.
  • The results of the sensitivity analyses also show a statistically significant difference for both operationalisations.
• Morbidity – Scoring Atopic Dermatitis (SCORAD 75 and SCORAD 90)
  • A SCORAD 75 – or a SCORAD 90 – response is considered clinically relevant. A statistically significant difference in favour of dupilumab was observed for both response thresholds (SCORAD 75 and SCORAD 90) (SCORAD 75: RR 2.25; 95% CI [1.57; 3.22]; p < 0.001; SCORAD 90: RR 1.77; 95% CI [0.89; 3.54]; p < 0.119).
  • Among patients treated with dupilumab, 39.4% achieved a SCORAD 75 response at week 52; in contrast, only 17.5% of patients treated with placebo plus TCS achieved a SCORAD 75. At week 52, 12.1% of patients in the relevant dupilumab arm and 6.8% of patients in the placebo+TCS arm achieved a SCORAD 90.
  • The results of the sensitivity analyses also show a statistically significant difference for both operationalisations.
• Morbidity – sleep disturbances (SCORAD-VAS)
  • For the mean change in the patient-relevant endpoint of sleep disturbances, a statistically significant, positive effect was observed in favour of dupilumab+TCS compared with placebo+TCS (-4.1 vs. -2.9, MD -1.2 [95% CI -1.6; -0.7]; p < 0.001). This represents a clinically relevant effect.
• Morbidity – Patient-reported symptoms (POEM)
  • For the mean change in patient-reported symptoms, a statistically significant, clinically relevant, positive effect was observed in favour of dupilumab + TCS compared with placebo + TCS (-13.8 vs. -6.7, MD -7.0 [95% CI -8.5; -5.6]; p < 0.001).
• Morbidity – Health status (EQ-5D VAS)
  • For the health status endpoint (EQ-5D VAS), a statistically significant difference in favour of dupilumab was observed for the mean change at week 52 compared with baseline. (21.4 vs. 15.2; MD 6.2 [95% CI 2.46; 9.85]; p < 0.001). However, the clinical relevance of this effect cannot be conclusively assessed, as the 95% CI of the standardised mean difference does not lie entirely outside the irrelevance range of –0.2 to 0.2 (Hedges’ g: 0.37 [0.15; 0.59]).
• Quality of life – Dermatology Life Quality Index (DLQI) response
  • For the proportion of patients with a DLQI of 0 or 1, a statistically significant advantage was observed for dupilumab (45.5% of patients) compared with placebo plus TCS (17.8% of patients) at week 52 (RR 2.55; 95% CI [1.82; 3.58]; p < 0.001).
• Side effects – Serious adverse events (SAEs)
  • Within the treatment groups, there were no statistically significant differences between dupilumab+TCS and placebo+TCS for the SAE endpoint.
• Side effects – Discontinuation due to adverse events (AE)
  • Although there is a statistically significant difference for the endpoint of discontinuation due to AEs, the effect is considered to be no more than minor (RR 0.33; 95% CI [0.10; 1.07]; p < 0.049).
• Overall assessment
  • The CHRONOS study provides results comparing dupilumab with placebo plus topical corticosteroids (TCS) in terms of mortality, morbidity, quality of life and side effects for the benefit assessment of dupilumab in the treatment of moderate to severe atopic dermatitis in adult patients eligible for systemic therapy.
  • In summary, based on the data presented, under the endpoint category of morbidity, a statistically significant advantage in favour of dupilumab plus TCS over placebo plus TCS was observed for the symptoms of pruritus and sleep disturbances, patient-reported symptoms, health status, a 75 per cent improvement in the EASI score, and 90 per cent, and an improvement in the SCORAD score of 75 per cent, a statistically significant advantage in favour of dupilumab+TCS compared with placebo+TCS.
  • Similarly, in the quality of life endpoint category, a statistically significant advantage in favour of dupilumab + TCS over placebo + TCS is observed in terms of achieving a DLQI of 0 or 1.
  • In the category of side effects, treatment with dupilumab showed disadvantages with regard to the endpoints of eye diseases and conjunctivitis.
  • Thus, there are positive effects on morbidity and quality of life, as well as a disadvantage in terms of side effects. However, these negative effects do not call into question the considerable positive effects of dupilumab.
  • Overall, the positive effects of dupilumab on all morbidityendpoints and on health-related quality of life, compared with the appropriate comparator therapy, are assessed as a significant improvement in treatment-related benefit that has not been achieved to date, and the extent of the additional benefit is classified as considerable.

Courtesy translation only, please refer to the German original.