Ixekizumab (1) – Taltz®

• Clinical trials
  • The benefit assessment is based on the randomised, controlled study RHBZ, submitted by the pharmaceutical manufacturer, which had a study duration of 24 weeks. This is a multicentre, open-label, actively controlled, three-arm Phase III trial comparing ixekizumab with the appropriate comparator therapy, methotrexate or fumaric acid esters in patients with moderate to severe plaque psoriasis who had not previously received systemic therapy.
  • The benefit assessment is based on the interim analysis at week 24, submitted by the pharmaceutical manufacturer, from the ongoing, randomised, double-blind, parallel-group study IXORAS (RHBS). This is a multicentre, actively controlled, two-arm Phase IIIstudy comparing ixekizumab with the appropriate comparator therapy, ustekinumab, in patients with moderate to severe plaque psoriasis who had experienced treatment failure, a contraindication or intolerance to at least one systemic therapy, including methotrexate, cyclosporine or phototherapy.

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

• There is an indication of a considerable additional benefit of ixekizumab compared with the appropriate comparator therapy, fumaric acid esters.
• Overall, the positive effects of ixekizumab 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 not previously achieved, and the extent of the additional benefit is classified as considerable.
• Overall, therefore, an indication is derived regarding the certainty of the findings.
• mortality
  • In the mortality category, no events occurred up to treatment week 24 in the RHBZ study.
• Morbidity – Psoriasis Area and Severity Index (PASI)
  • 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 disease severity in clinical practice.
  • Remission (PASI 100) By week 24, 60% of patients in the ixekizumab arm achieved PASI 100 and thus complete remission; in the fumaric acid ester arm, by contrast, the figure was only 2.3%. When considering the median time to achieving PASI 100, there is a statistically significant advantage in favour of ixekizumab (HR 18.40 [95% CI 2.49; 136.19]; p-value = 0.004).
  • PASI 75 and PASI 90 responses For both response thresholds (PASI 75 and PASI 90), statistically significant differences in favour of ixekizumab were observed in terms of the median time to achieving a PASI 75 or 90 response (PASI 75: HR 20.80 [95% CI 8.16; 53.07]; p-value < 0.001; PASI 90: HR 21.72 [95% CI 6.54; 72.14]; p-value < 0.001).
• Morbidity – Symptom -free status in the face/neck
  • 68% of patients in the ixekizumab arm achieved freedom from lesions on the face/neck, compared with 21% in the fumaric acid ester arm. The time-to-event analysis for this endpoint showed a statistically significant advantage of ixekizumab over fumaric acid esters (HR 3.00 [95% CI 1.41; 6.38]; p-value = 0.004).
• Morbidity – freedom from genital symptoms
  • No statistically significant difference was observed between the treatment groups for this endpoint.
• Morbidity – freedom from symptoms in the nail area – measured using the NAPPA-CLIN score
  • The sponsor did not provide any usable data for the endpoint ‘nail involvement’, as assessed using the Nail Assessment in Psoriasis and Psoriatic Arthritis – Clinical Assessment of Severity (NAPPA-CLIN).
• Morbidity – Symptom-free itch – measured using a Numeric Rating Scale (NRS)
  • For the proportion of patients who achieved a reduction in itching of ≥ 4 points by week 24, ixekizumab showed an advantage compared with fumaric acid ester (78% in the ixekizumab arm vs. 47% in the fumaric acid ester arm). Analysis of the endpoint as the time to achieving a reduction in pruritus of ≥ 4 points also shows a statistically significant difference in favour of ixekizumab (28 days in the ixekizumab arm vs. 92 days in the fumaric acid ester arm; HR 1.96 [95% CI 1.11; 3.47]; p-value = 0.020).
• Morbidity – Symptoms of skin pain measured using a visual analogue scale (VAS)
  • When considering the mean change in skin pain from baseline to week 24, there is a statistically significant advantage for ixekizumab compared with fumaric acid ester (MD −16.35 [95% CI −25.72; −6.98]; p-value < 0.001). The effect can be classified as relevant, as the 95% confidence interval of the standardised mean difference lies entirely outside the irrelevance range of −0.2 to 0.2 (Hedge’s g: −0.96 [95% CI −1.55; −0.38]).
• Morbidity – Health status assessed using the EQ-5D VAS
  • No statistically significant advantage or disadvantage of ixekizumab over fumaric acid esters can be inferred.
• Quality of life – Dermatology Life Quality Index (DLQI) response
  • Analyses of the median time to reaching a DLQI of 0 or 1 indicate a statistically significant advantage for ixekizumab compared with fumaric acid esters (86 days in the ixekizumab arm versus 173 days in the fumaric acid ester arm; HR 2.77 [95% CI 1.30; 5.92], p-value = 0.008). Analyses of the proportion of patients who achieved a DLQI of 0 or 1 at week 24 show a similar advantage in favour of ixekizumab, with a comparable effect size (68% in the ixekizumab arm vs. 21% in the fumaric acid ester arm).
• Side effects – AE and SAE
  • No difference was observed between the intervention arms of the RHBZ study for the patient-relevant endpoint of AEs. No usable data are available for SAE.
• Side effects – discontinuation due to AEs
  • For the patient-relevant endpoint ‘discontinuation due to AEs’, there was a statistically significant advantage of ixekizumab compared with fumaric acid ester (3% in the ixekizumab arm vs. 39% in the fumaric acid ester arm (RR 0.06 [95% CI 0.01; 0.46], p-value < 0.001)).
• Side effects – specific AEs
  • No usable data are available for specific AEs or the endpoint ‘infections and parasitic diseases’.
• Overall assessment
  • For patients with moderate to severe plaque psoriasis who are eligible for systemic therapy, a considerable, statistically significant benefit in favour of ixekizumab over the standard comparator therapy, fumaric acid ester, was demonstrated in the endpoint categories of remission – as measured by both PASI 100 and an improvement in the PASI score of 75 per cent or 90 per cent, as well as in the symptom endpoints ‘absence of lesions on the face/neck’ and ‘skin pain’, a considerable, statistically significant advantage in favour of ixekizumab compared with the appropriate comparator therapy, fumaric acid esters.
  • A positive effect in favour of ixekizumab is also evident for the symptom of pruritus. In the health-related quality of life endpoint category, there are likewise clear positive effects, providing proof of an advantage of ixekizumab over fumaric acid esters.
  • In the category of side effects, ixekizumab showed advantages over fumaric acid esters when considering the safety endpoint ‘discontinuation due to AEs’, whilst neither advantages nor disadvantages could be inferred from the AEs associated with ixekizumab.

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

• For patients who have responded inadequately to other systemic therapies, including ciclosporin, methotrexate or PUVA (psoralen and ultraviolet A light), or who have a contraindication to or are intolerant of such therapies (Patient population B), there is an indication of a minor additional benefit for ixekizumab compared with the appropriate comparator therapy, ustekinumab.
• On balance, the effects of ixekizumab are therefore assessed as a moderate—and not merely minor—improvement in treatment-related benefit, as defined in Section 2(3), which has not yet been achieved compared with the appropriate comparator therapy, and the extent of the additional benefit is classified as minor.
• Overall, therefore, an indication is drawn regarding the certainty of the findings.
• mortality
  • In the mortality category, no events had occurred up to the interim analysis at week 24.
• Morbidity – Remission (PASI 100)
  • By week 24, 49% of patients in the ixekizumab arm achieved PASI 100 and thus complete remission; in the ustekinumab arm, by contrast, the figure was only 23%. There is a statistically significant advantage in favour of ixekizumab (RR 2.10 [95% CI 1.52; 2.90]; p-value < 0.001).
• Morbidity – PASI 75 and PASI 90 response
  • For both response thresholds (PASI 75 and PASI 90), statistically significant differences in favour of ixekizumab were observed in the proportion of patients achieving a response at week 24 (PASI 75: 91% in the ixekizumab arm vs. 82% in the ustekinumab arm: RR 1.11 [95% CI 1.02; 1.22]; p-value = 0.023; PASI 90: 83% in the ixekizumab arm vs. 59% in the ustekinumab arm: RR 1.41 [95% CI 1.21; 1.63]; p-value < 0.001).
• Morbidity – absence of symptoms in fingernails/nail involvement – measured using the Nail Psoriasis Severity Index (NAPSI)
  • A reduction in NAPSI of 100 per cent (NAPSI 100), which indicates a complete resolution of nail psoriasis, is considered clinically relevant. For NAPSI 100 in patients who had nail involvement at the start of the study, a statistically significant difference in favour of ixekizumab compared with ustekinumab (51% in the ixekizumab arm vs. 25% in the ustekinumab arm: RR 2.28 [95% CI 1.27; 3.29]; p-value = 0.021).
• Morbidity – absence of symptoms on the face/neck or in the genital area
  • No statistically significant differences between the treatment groups were observed for this endpoint, neither for the face/neck nor for the genital area.
• Morbidity – Symptoms of pruritus – measured using a Numeric Rating Scale (NRS)
  • When considering the mean change in itching (NRS score) from baseline to week 24, there was no statistically significant difference for ixekizumab compared with ustekinumab for this endpoint.
• Morbidity – Symptoms: Skin pain measured using a Visual Analogue Scale (VAS)
  • Based on the mean change in the VAS score from baseline to week 24, no statistically significant advantage or disadvantage of ixekizumab over ustekinumab can be inferred for this endpoint.
• Morbidity – Health status as measured by the EQ-5D VAS
  • There is a statistically significant advantage for the ixekizumab intervention compared with ustekinumab (MD 4.46 [95% CI 0.45; 8.66]; p-value = 0.03). The effect cannot be classified as relevant, as the 95% confidence interval for the standardised mean difference does not lie entirely outside the irrelevance range of –0.2 to 0.2 (Hedge’s g: 0.25 [95% CI 0.02; 0.48]).
• Quality of life – Dermatology Life Quality Index (DLQI) response
  • Analyses of the proportion of patients who achieved a DLQI of 0 or 1 at week 24 showed a statistically significant advantage in favour of ixekizumab compared with ustekinumab (66% vs. 53%; RR 1.25 [95% CI 1.04; 1.50]; p-value = 0.022).
• Quality of life – Health Survey Short Form 36 (SF-36)
  • The additional responder analyses conducted by the pharmaceutical manufacturer could not be taken into account, as the derivation of the MID for the SF-36 (MCS and PCS) was not sufficiently justified (see comments on Population A).
  • A statistically significant advantage for the ixekizumab intervention compared with ustekinumab is evident for the physical health subscale (PCS) (MD 1.93 [95% CI 0.49; 3.37]; p-value = 0.009). The effect cannot be classified as relevant, as the 95% confidence interval for the standardised mean difference does not lie entirely outside the irrelevance range of –0.2 to 0.2 (Hedge’s g: 0.31 [95% CI 0.08; 0.54]).
• Side effects – AE and SAE
  • No statistically significant differences were observed between the intervention arms of the IXORAS study for the patient-relevant endpoints AEs and SAE.
• Side effects – discontinuation due to AEs
  • For the patient-relevant endpoint of discontinuation due to AEs, there was also no statistically significant advantage or disadvantage of ixekizumab compared with ustekinumab.
• Overall assessment
  • For patients who have responded inadequately to other systemic therapies, including ciclosporin, methotrexate or PUVA (psoralen and ultraviolet A light), or who have a contraindication to or intolerance of such therapies, there is evidence of a statistically significant advantage in favour of ixekizumab over the appropriate comparator, ustekinumab, both in the endpoint categories of remission as measured by PASI 100 and NAPSI 100, and in the improvement in the PASI score by 75 per cent or 90 per cent, a statistically significant advantage in favour of ixekizumab over the appropriate comparator therapy, ustekinumab.
  • In the morbidity category, the disease-specific symptoms of skin pain and itching – which are significant in plaque psoriasis – were assessed. However, no significant differences between the two study arms were observed for these symptoms.
  • In the endpoint category of health-related quality of life, as measured by the DLQI, positive effects were observed, providing proof of an advantage of ixekizumab over ustekinumab.
  • In the ‘Side effects’ category, no advantages or disadvantages of ixekizumab compared with ustekinumab were observed when considering AEs, SAEs and discontinuation due to AEs. For the specific side effect ‘General disorders and administration site conditions’, ixekizumab was associated with greater harm compared with ustekinumab; however, this does not call into question the positive effects observed in the morbidity and quality of life categories.

Courtesy translation only, please refer to the German original.