Brodalumab (1) – Kyntheum®

• Clinical trials
  • Both studies included adult patients with stable, moderate to severe plaque psoriasis.

a) adult patients with moderate to severe plaque psoriasis who are eligible for systemic therapy

• An additional benefit is not proven.
• The pharmaceutical manufacturer has submitted data from an adjusted indirect comparison based on the AMAGINE-1, AMAGINE-2 and AMAGINE-3 studies on brodalumab over a 12-week period and the BRIDGE study on fumaric acid esters over a 16-week period.
• However, in the context of this chronic condition, a study duration of at least 24 weeks is considered necessary to assess additional benefit.
• Consequently, the indirect comparison of brodalumab with fumaric acid esters submitted by the pharmaceutical manufacturer cannot be used for the benefit assessment due to the treatment duration being too short.
• Consequently, no usable data are available.

b) adult patients with moderate to severe plaque psoriasis who have had an inadequate response to other systemic therapies, including ciclosporin, methotrexate or oral PUVA (psoralen and ultraviolet A light), or who have a contraindication to or are intolerant of such therapies

• There is an indication of a non-quantifiable additional benefit of brodalumab compared with the appropriate comparator therapy, ustekinumab.
• Taking the results as a whole, the G-BA classifies the additional benefit as non-quantifiable.
• Overall, therefore, despite the availability of two randomised, double-blind, head-to-head comparative studies, the certainty of the evidence is classified as ‘indication’.
• mortality
  • In both studies, no deaths occurred during treatment with brodalumab up to week 52.
  • Under treatment with ustekinumab, 2 deaths were recorded in the AMAGINE-2 study and no deaths were recorded in the AMAGINE-3 study.
• Morbidity – Psoriasis Area and Severity Index (PASI)
  • In this assessment, morbidity is presented in terms of remission (PASI 100), response (PASI 75 or PASI 90) and patient-reported symptoms (PSI).
  • In the German healthcare context, the PASI is a standard tool used by doctors to assess disease severity and is of great relevance for diagnosis and monitoring the progression of the disease during treatment.
  • Remission (PASI 100)
  • Remission (PASI 100) is considered to be of clinical relevance to patients.
  • The NRI analyses of the AMAGINE-2 and AMAGINE-3 studies show a statistically significant advantage in favour of brodalumab over ustekinumab (meta-analysis: RR 2.26 [95% CI 1.74; 2.92]; p-value < 0.001).
  • At week 52, 52% of patients in the AMAGINE-2 study and 46% of patients in the AMAGINE-3 study achieved remission whilst on brodalumab; in contrast, only 22% and 21% of patients, respectively, achieved remission in the ustekinumab arm.
  • The results of the sensitivity analyses continue to show a statistically significant advantage in favour of brodalumab, despite a reduced effect size (meta-analysis: RR 1.49 [95% CI 1.18; 1.88]; p-value < 0.001).
  • PASI 75 and PASI 90 response
  • A PASI 75 or PASI 90 response is considered clinically relevant.
  • NRI analyses reveal a statistically significant difference in favour of brodalumab for both response thresholds (PASI 75 and PASI 90) (PASI 75 meta-analysis: RR 1.51 [95% CI 1.27; 1.80]; p-value < 0.001; PASI 90 meta-analysis: RR 1.81 [95% CI 1.49; 2.21]; p-value < 0.001).
  • At week 52, 65 per cent (AMAGINE-2) and 58% (AMAGINE-3) of patients, respectively, achieved a PASI 75 response; by contrast, only 40% and 42% of patients, respectively, achieved a PASI 75 response whilst on ustekinumab.
  • At week 52, 63% and 57% of patients in the brodalumab arm, and 33% and 34% in the ustekinumab arm, achieved a PASI 90 response.
  • The results of the sensitivity analyses show only a statistically significant difference in favour of brodalumab in terms of achieving the PASI 90 response threshold (meta-analysis: RR 1.26 [95% CI 1.05; 1.50]; p-value < 0.012).
• Health-related quality of life – Dermatology Life Quality Index (DLQI) response
  • The DLQI is a validated questionnaire used to assess disease-specific health-related quality of life in adult patients with dermatological conditions.
  • For the proportion of patients with a DLQI of 0 or 1, NRI analyses at week 52 show a statistically significant advantage for brodalumab (53% (AMAGINE-2) and 51% (AMAGINE-3) of patients) compared with ustekinumab (33% and 36% of patients, respectively); (meta-analysis: RR 1.52 [95% CI 1.23; 1.87]; p-value < 0.001).
  • The results of the sensitivity analyses, however, show no statistically significant difference between brodalumab and ustekinumab in terms of achieving a DLQI of 0 or 1.
• Side effects – severe adverse events (SAEs)
  • For the endpoint of serious adverse events, the results are heterogeneous and do not show consistent effects.
  • These data provide no hint of greater or minor harm from brodalumab compared with ustekinumab for the SAE endpoint.
• Overall assessment
  • For patients who have responded inadequately to other systemic therapies, including ciclosporin, methotrexate or oral PUVA (psoralen and ultraviolet A light), or who have a contraindication to or intolerance of such therapies, the NRI analyses from the AMAGINE-2 and AMAGINE-3 trials, under the endpoint category of morbidity in remission (PASI 100), a statistically significant advantage in favour of brodalumab over the appropriate comparator therapy, ustekinumab, in terms of a 75% or 90% improvement in the PASI score and the achievement of a total PSI score of ≤ 8.
  • Similarly, in the quality of life endpoint category, a statistically significant advantage in favour of brodalumab over ustekinumab was observed when a DLQI of 0 or 1 was achieved.
  • Taking into account the sensitivity analyses, which employed a more conservative substitution strategy for the analysis of the AMAGINE-2 and AMAGINE-3 studies, a statistically significant advantage of brodalumab over ustekinumab was observed only in remission (PASI 100) and in the 90% improvement in the PASI score, whilst the effect size for both endpoints is significantly reduced compared with the NRI analyses.
  • In terms of side effects, there are neither advantages nor disadvantages of brodalumab compared with ustekinumab that can be used to infer any additional benefit.
  • Overall, therefore, both the results of the NRI analyses and those of the sensitivity analyses show an advantage over the appropriate comparator therapy, ustekinumab.
  • Whilst the statistical approach of the NRI analyses highlights the maximum possible therapeutic effects of brodalumab, the sensitivity analyses provide a significantly more conservative estimate in this regard.
  • It should be noted that assumptions were made for both approaches to account for the very high proportion of values requiring replacement.
  • It is therefore not possible to conclusively assess the extent of the demonstrated additional benefit of brodalumab compared with the appropriate comparator therapy, ustekinumab.

Courtesy translation only, please refer to the German original.