Guselkumab (1) – Tremfya®

• Clinical trials
  • The benefit assessment is based on the randomised, controlled POLARIS trial (n=119) submitted by the pharmaceutical manufacturer, with a primary study duration of 24 weeks (Part 1 of the trial). This is a two-arm, open-label, randomised, actively controlled Phase IIIstudy comparing guselkumab with the appropriate comparator therapy, fumaric acid esters, in adult patients with moderate to severe plaque psoriasis who had not previously received systemic therapy.
  • The benefit assessment for patient population B is based on the two double-blind, randomised studies, VOYAGE1 and VOYAGE2, as well as the meta-analysis of both studies at week 24. The VOYAGE1 and VOYAGE2 studies were randomised, double-blind trials involving adults with moderate to severe plaque psoriasis who were eligible for systemic therapy or phototherapy and who were either systemic therapy-naïve or had previously been treated with a systemic therapy. In the relevant study arms, guselkumab was compared with adalimumab.

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

• For adult patients with moderate to severe plaque psoriasis who are eligible for systemic therapy, there is an indication for a considerable additional benefit of guselkumab compared with the appropriate comparator therapy, fumaric acid esters.
• Overall, therefore, an indication is derived for the certainty of the evidence.
• mortality
  • In the mortality category, no events occurred up to treatment week 24 in the POLARIS study.
• Morbidity – Remission (PASI 100)
  • Remission (PASI 100) is considered to be of clinical relevance to patients. At week 24, 33.5% of patients in the guselkumab arm achieved PASI 100 and thus complete remission; in the fumaric acid ester arm, by contrast, the figure was only 4.9%. When considering the median time to achieving PASI 100, there is a statistically significant advantage in favour of guselkumab (HR 10.50 [95% CI 2.48; 44.56]; p-value = 0.001).
  • Remission was assessed on a single cut-off date only. However, an operationalisation limited to fixed analysis time points cannot adequately reflect the fluctuating course of this disease.
• Morbidity – PASI 75 and PASI 90 response
  • A PASI 75 or PASI 90 response is considered clinically relevant. For both response thresholds (PASI 75 and PASI 90), statistically significant differences were observed in favour of guselkumab with regard to the median time to achieving a PASI 75 or 90 response (PASI 75: HR 7.47 [95% CI 3.87; 14.41]; p-value < 0.001; PASI 90: HR 4.51 [95% CI 2.80; 7.25]; p-value < 0.001).
• Morbidity – patient-reported symptoms – assessed using the PSSD, absence of symptoms on the scalp (ss-IGA 0)
  • Both patient-reported symptoms using the Psoriasis Symptom and Sign Diary (PSSD) and the presence of plaque psoriasis on the scalp were recorded in the POLARIS study; however, at the time of the dossier submission, no analyses were provided either on patient-relevant freedom from symptoms on the scalp (ss-IGA 0) or on patient-relevant psoriasis symptoms. The data submitted subsequently by the pharmaceutical manufacturer during the commenting procedure could have been provided at the time of the dossier submission; these are therefore not taken into account for the benefit assessment.
• 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 guselkumab compared with fumaric acid esters (133 days in the guselkumab arm versus 173 days in the fumaric acid ester arm; HR 3.29 [95% CI 1.75; 6.16], p-value < 0.001). Analyses of the proportion of patients who achieved a DLQI of 0 or 1 by week 24 show a similar advantage of comparable magnitude in favour of guselkumab (67% in the guselkumab arm versus 28% in the fumaric acid ester arm).
• Quality of life – Health Survey Short Form 36 (SF-36) physical summary score
  • The analyses of the mean change in the SF-36 physical summary score from baseline to week 24 of treatment showed a statistically significant advantage for guselkumab over the comparator intervention, fumaric acid esters (MD 4.80 [2.09; 7.52]; p-value < 0.001). The 95% confidence interval for the standardised mean difference lies entirely outside the non-significant range of –0.2 to 0.2 (SMD: 0.63 [0.26; 1.00]), meaning that the advantage of guselkumab in terms of an improvement in the physical total score compared with fumaric acid esters is to be regarded as clinically relevant.
• Quality of life – Health Survey Short Form 36 (SF-36) mental health summary score
  • Contrary to the results for the SF-36 physical total score, the analyses of the mean change in the SF-36 mental health total score from baseline to week 24 do not indicate any statistically significant effect in favour of either treatment regimen.
• Side effects – SAE
  • For the patient-relevant endpoint SAE, no statistically significant advantage or disadvantage was observed for guselkumab compared with the comparator intervention in the POLARIS study.
• Side effects – discontinuation due to AEs
  • For the patient-relevant endpoint ‘discontinuation due to AEs’, there was a statistically significant advantage of guselkumab compared with fumaric acid ester (0% in the guselkumab arm vs. 28% in the fumaric acid ester arm (RR 0.03 [95% CI 0.00; 0.48], p-value < 0.001).
• Side effects – specific AEs
  • For the endpoint ‘infections and parasitic diseases’, no statistically significant difference was observed between the treatment arms. For other specific AEs – for the endpoints ‘gastrointestinal disorders’ and ‘feeling of heat’ – a statistically significant effect was observed in favour of guselkumab compared with fumaric acid esters.
• Overall assessment
  • For patients with moderate to severe plaque psoriasis who are eligible for systemic therapy, a considerable, statistically significant advantage in favour of guselkumab over the standard comparator therapy, fumaric acid esters, was demonstrated in the endpoint categories of remission – as measured by PASI 100 – and in the improvement in the PASI score by 75 per cent and 90 per cent, a considerable, statistically significant advantage in favour of guselkumab compared with the appropriate comparator therapy, fumaric acid esters. In the health-related quality of life endpoint category, there are also clear positive effects, providing proof of an advantage of guselkumab over fumaric acid esters. In the category of side effects, guselkumab showed advantages over fumaric acid esters not only in terms of the safety endpoint ‘discontinuation due to AEs’ but also for the specific AEs ‘gastrointestinal disorders’ and ‘feeling of heat’.
  • Overall, the positive effects of guselkumab on the morbidity endpoints investigated, on health-related quality of life and on the adverse reaction profile 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.

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

• For adult patients with moderate to severe plaque psoriasis 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, there is proof of considerable additional benefit for guselkumab compared with the appropriate comparator therapy, adalimumab.
• Overall, based on two randomised, double-blind, head-to-head comparative trials, the certainty of evidence is classified as ‘one level of proof’.
• mortality
  • In the mortality category, no events occurred up to treatment weeks 24 and 28, respectively, in the VOYAGE1 and 2 studies.
• Morbidity – Remission (PASI 100)
  • Remission (PASI 100) is considered to be of clinical relevance. At week 24, an average of 45% of patients in the guselkumab arm achieved PASI 100 and thus complete remission; in the adalimumab arm, by contrast, the figures were only 24% and 28%, respectively. The effect is statistically significant in favour of guselkumab, both for the individual studies and for the meta-analysis of both studies (overall RR 1.70 [95% CI 1.37; 2.11]; p-value < 0.01). When considering the median time to achieving PASI 100, there is also a statistically significant advantage in favour of guselkumab, both at the individual study level and based on the meta-analysis of both studies at week 24 (overall HR 1.89 [95% CI 1.48; 2.42]; p-value < 0.01).
  • Furthermore, the Week 48 data from the VOYAGE1 study show that the observed positive effects of guselkumab compared with adalimumab persist in magnitude beyond Week 24, hinting at continued effects up to Week 48 (RR 1.90 [95% CI 1.45; 2.49]; p-value < 0.001).
• Morbidity – PASI 75 and PASI 90 response
  • A PASI 75 or PASI 90 response is also considered clinically relevant. Based on the proportion of patients showing an improvement in their PASI score from baseline to week 24 of 75 per cent (PASI 75) or 90 per cent (PASI 90) from the start of the study to week 24, statistically significant advantages for guselkumab over adalimumab can be inferred both at the level of individual studies and in the meta-analysis (PASI 75: overall RR 1.23 [95% CI 1.15; 1.32]; p-value < 0.01; PASI 90: overall RR 1.35 [95% CI 1.22; 1.49]; p-value < 0.01). Similarly, for both response thresholds (PASI 75 and PASI 90) regarding the median time to achieving a PASI 75 or 90 response, both in the individual studies and in the meta-analysis at week 24, there were statistically significant differences in favour of guselkumab (PASI 75: overall HR 1.26 [95% CI 1.07; 1.49]; p-value < 0.01; PASI 90: overall HR 1.62 [95% CI 1.35; 1.95]; p-value < 0.01).
  • It is also worth noting, in support of the PASI 90 and PASI 75 analyses, that the PASI data at week 48 from VOYAGE 1 (PASI 75: HR 1.28 [95% CI 1.45; 2.57]; p-value < 0.001; PASI 90: HR 1.44 [95% CI 1.12; 1.84]; p-value < 0.001) corroborate the results of the meta-analysis in favour of guselkumab.
• Quality of life – Dermatology Life Quality Index (DLQI) response
  • For general information on the DLQI, please refer to Population A. Analyses of the median time to achieving a DLQI of 0 or 1 indicate a statistically significant effect in favour of guselkumab compared with adalimumab at week 24, both for the individual VOYAGE studies and for the meta-analysis of both studies (overall HR 1.44 [95% CI 1.16; 1.78], p-value < 0.01). Similarly, the analyses of the proportion of patients who achieved a DLQI of 0 or 1 at week 24 show a consistent advantage for guselkumab over treatment with adalimumab, both for the individual studies and for the meta-analysis (overall RR 1.47 [95% CI 1.25; 1.72], p-value < 0.01).
  • At week 48, too, the analyses from VOYAGE1 confirm a sustained advantage of similar magnitude in favour of guselkumab: the proportion of patients who achieved a DLQI of 0 or 1 at week 48 (61% in the guselkumab arm versus 45% in the adalimumab arm) is statistically significant in favour of guselkumab (RR 1.36 [95% CI 1.11; 1.66], p-value = 0.002).
• Side effects – SAE
  • For the patient-relevant endpoint SAE, neither study showed any statistically significant advantage or disadvantage for guselkumab compared with the comparator intervention at week 28. Similarly, at week 48, based on the analyses of the VOYAGE1 study, there are no indications of differences between the treatment arms.
• Overall assessment
  • For 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, a statistically significant advantage in favour of guselkumab over the appropriate comparator therapy, adalimumab, is evident in the remission endpoints, as measured by both the PASI 100 and improvements in the PASI score of 75% and 90% respectively. This effect is complemented by further statistically significant benefits in favour of guselkumab in terms of patient-reported symptoms, which can be derived both from the results of the NRI analysis and from the (more conservative) sensitivity analyses. In the endpoint category of health-related quality of life, there are also clear positive effects, providing proof of an advantage of guselkumab over adalimumab. In the category of side effects, there is currently neither an advantage nor a disadvantage for guselkumab compared with adalimumab.
  • Overall, the positive effects of guselkumab on the morbidityendpoints, as well as on health-related quality of life, without any disadvantages in the adverse effect profile 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.