Ixekizumab (2) – Taltz®

• Clinical trials
  • The benefit assessment is based on the randomised, double-blind, actively controlled RHAP trial submitted by the pharmaceutical manufacturer.

a) Adult patients with active psoriatic arthritis who are eligible for treatment with a conventional DMARD other than methotrexate

• An additional benefit is not proven.
• The pharmaceutical manufacturer has not provided any data for this patient population, meaning that no conclusions can be drawn regarding the additional benefit of ixekizumab compared with the appropriate comparator therapy.

b) Adult patients with active psoriatic arthritis who are bDMARD-naïve and for whom first-line therapy with bDMARDs is indicated

• There is a hint of a minor additional benefit of ixekizumab compared with the appropriate comparator therapy, adalimumab.
• mortality
  • No deaths occurred in the relevant patient population during the study period.
• Morbidity – Minimal Disease Activity (MDAPASI)
  • For the endpoint of minimal disease activity assessed using the MDAPASI, there was no statistically significant difference between the treatment groups.
• Morbidity – Physical functional status (HAQ-DI)
  • For the endpoint of physical functional status, as assessed by the HAQ-DI, there was no statistically significant difference between the treatment groups.
• Morbidity – Skin symptoms (PASI 75, 90 and 100)
  • Skin symptoms were assessed in the RHAP study using the Psoriasis Area and Severity Index.
  • Both in terms of remission of skin symptoms (PASI 100) and the PASI 90 response, there was a statistically significant advantage in favour of ixekizumab over adalimumab (PASI 100: RR 1.92 [95% CI 1.06; 3.50]; p-value = 0.029; PASI 90: RR 2.04 [95% CI 1.20; 3.46]; p-value = 0.006). In contrast, no statistically significant differences were observed in the PASI 75 response.
• Morbidity – Enthesitis (Leeds Enthesitis Index, LEI)
  • Enthesitis was assessed in the RHAP study using the Leeds Enthesitis Index.
  • For the endpoint of enthesitis, a statistically significant advantage in favour of ixekizumab was observed in terms of the change in the number of tender tendon insertion points from the start of the study to week 24. Based on the mean difference, an improvement of 0.60 tendon insertion points was observed with ixekizumab therapy compared with the adalimumab arm (MD −0.60 [95% CI −1.08; −0.12]; p-value = 0.014).
• Morbidity – dactylitis (Leeds Dactylitis Index-Basic, LDI-B)
  • For the endpoint of dactylitis, as assessed using the Leeds Dactylitis Index-Basic, no statistically significant difference was observed between the treatment groups.
• Morbidity – Health status (EQ-5D VAS)
  • For the health status endpoint, assessed using the EQ-5D VAS, there was no statistically significant difference between the treatment groups.
• Quality of life – Dermatology Life Quality Index (DLQI)
  • No statistically significant difference was observed between the treatment groups for the DLQI.
• Side effects – severe adverse events (SAE) and discontinuation due to adverse events (AE)
  • For the endpoints SAE and discontinuation due to AEs, no statistically significant difference was observed between the treatment groups in either case.
• Overall assessment
  • The benefit assessment was based on the randomised, double-blind, actively controlled RHAP trial, in which ixekizumab was compared with adalimumab.
  • For ixekizumab, statistically significant advantages were observed in the morbidity endpoints of skin symptoms (remission defined as PASI 100 and PASI 90 response) and the number of tender tendon insertion points (enthesitis).
  • However, no statistically significant differences between the treatment groups were observed in any of the other morbidity endpoints assessed, nor in the endpoint categories of health-related quality of life and side effects in the form of SAEs and discontinuation due to AEs.
  • For the specific AEs ‘general disorders and administration site conditions’, ixekizumab was found to have a disadvantage compared with adalimumab.
  • However, it is difficult to assess the significance of the advantages in terms of PASI 100 and PASI 90, as the analysis exclusively included patients with mild plaque psoriasis; consequently, the patient cohort was not representative for the endpoint of skin symptoms.
  • Similarly, the disadvantages of ixekizumab in terms of ‘general disorders and administration site conditions’ are not relevant to the assessment of additional benefit, as these are classified as non-serious.
  • The statistically significant effects of ixekizumab on the enarthritis endpoint are classified as minor in extent.
  • Furthermore, there are no statistically significant differences in the endpoints of the number of tender and swollen joints, joint pain, disease activity, physical functional status, health status and health-related quality of life.
  • It is assumed that improvements in the number of tender tendon insertion points beyond a minor level would also have shown positive effects on at least some other patient-reported endpoints.
  • On balance, the effects of ixekizumab are therefore assessed as a moderate – rather than merely minor – improvement in treatment-relevant benefit compared with the appropriate comparator therapy, as defined in Section 2(3), and the extent of the additional benefit is classified as minor.
  • The assessment of the additional benefit is based on a randomised, double-blind and direct-comparison study. However, only that subset of patients included in the study in which the medicinal products were used in accordance with the marketing authorisation and who, on the basis of their prior treatments, met the characteristics of the patient population under assessment could be used for the benefit assessment.
  • Consequently, of the original 208 patients included, only 51 patients in the ixekizumab arm and 56 patients in the adalimumab arm could be taken into account.
  • Furthermore, no usable data are available for patients with active psoriatic arthritis and concomitant moderate to severe plaque psoriasis, as these patients were not treated in accordance with the approved indications for psoriatic arthritis therapy over the 24-week study period.
  • Even though it cannot be assumed that this patient population differs fundamentally from the patient population under evaluation, the validity of the results presented is subject to uncertainty.
  • Furthermore, it should be noted that, as part of the commenting procedure, the pharmaceutical manufacturer submitted corrected analyses only for those endpoints where a statistically significant difference had already been demonstrated in the dossier.
  • Due to the differing analytical methods, a high potential for bias must be assumed. Overall, therefore, despite the availability of a randomised, double-blind and head-to-head comparative study, the certainty of the findings is classified as a hint.

c) Adult patients with active psoriatic arthritis who have responded inadequately to, or are intolerant of, prior treatment with disease-modifying biological anti-rheumatic drugs (bDMARDs)

• The additional benefit is not proven.
• The pharmaceutical manufacturer has not provided any data for this patient population; consequently, no conclusions can be drawn regarding the additional benefit of ixekizumab compared with the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.