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Management


ustekinumab versus etanercept,24


infliximab versus methotrexate.25 Speed of action


The speed of action of any treatment is of importance for both patients and physicians. The results of a meta-analysis of the weighted mean time until 25% of patients achieved a PASI75 response26 showed that it was shortest for infliximab (3.5 weeks), followed by ustekinumab (4.6 for 90mg, 5.1 for 45mg, not weight- adapted), adalimumab (4.6 weeks), and etanercept (6.6 high dose, 9.5 low dose). Among the conventional treatments, good data were available for ciclosporin A (6.0 weeks) and limited data for MTX (high dose 3.2, low dose 9.9 weeks). Secukinumab was superior to ustekinumab with respect to efficacy in the initial treatment period, with the PASI75 response rates at Week 4 in the 300mg secukinumab group being 50.0% versus 20.6% in the ustekinumab group.23


Drug survival


Drug survival (time to drug discontinuation) has emerged as an important parameter reflecting the long-term therapeutic performance in a real-life setting. Drug survival reflects a drug’s effectiveness, safety, and tolerability, but in psoriasis it is also driven by a phenomenon sometimes associated with long-term treatments, namely a gradual loss of efficacy over time. Data on biologic drug survival from two large national prospective registries have been published, one from Denmark27 and the other from the UK.28 The DERMBIO prospective registry covers all patients with psoriasis vulgaris treated with biologic agents in academic centres in Denmark. Included in the analysis were 1867 treatment series (adalimumab n=774; etanercept n=449; infliximab n=253; ustekinumab n=391) administered in 1277 patients for up to ten years. Drug survival was significantly longer for ustekinumab than for anti- tumour necrosis factor (TNF)-α agents (p<0.001). Etanercept had the shortest survival time (median survival 30 months, 95% CI 25.1–34.9) whereas adalimumab and infliximab had comparable survival rates (59 months, 95% CI 45.6–72.4; 44 months, 95% CI 33–54.9, respectively). Survival was longer in men (odds ratio (OR) 1·51, 95% CI 1.31–1.74 versus women) and in patients who had not previously received any biologic agent (OR 1.24, 95% CI


and of


1.05–1.46). Loss of efficacy accounted for 67% of all drug discontinuations.27 In the other study, the survival rates of the first course of biologics for 3523 biologic-naive patients with chronic plaque psoriasis included in a prospective national pharmacovigilance cohort (British Association of Dermatologists Biologic Interventions Register (BADBIR) were compared. Data for patients on adalimumab (n=1879), etanercept (n=1098), infliximab (n=96), and ustekinumab (n=450) were available. The overall survival rate in the first year was 77%, falling to 53% in the third year. Multivariate analysis showed that female gender (hazard ratio (HR) 1.22; 95%CI 1.09–1.37), being a current smoker (HR 1.19; 95% CI 1.03–1.38), and a higher baseline dermatology life quality index (HR 1.01; 95% CI 1.00–1.02) were predictors of discontinuation. Presence of PsA (HR 0.82; 95% CI 0.71–0.96) was a predictor of drug survival.28


Compared


with adalimumab, patients on etanercept (HR 1.63; 95%CI 1.45–1.84) or infliximab (HR 1.56; 95% CI: 1.16–2.09) were more likely to discontinue therapy, whereas patients on ustekinumab were more likely to persist (HR 0.48; 95% CI: 0.37–0.62). After accounting for relevant covariates, ustekinumab had the highest first-course drug survival.28


Immunogenicity Anti-drug antibodies (ADAs) are observed for all biologic drugs used in the treatment of psoriasis; however, several factors influence immunogenicity as not all patients appear to develop ADAs, and the frequency varies from one drug to another. ADAs have been reported in patients treated with etanercept, infliximab, adalimumab or ustekinumab at rates of 0–18.3%, 5.4–43.6%, 8.8– 44.8% and 3.8–5.4%, respectively.29 Many factors contribute to this unwanted immune response, including the product itself, its mode of administration, the underlying disease, and patient characteristics: patients who develop ADAs against a first TNF inhibitor are more likely to develop ADAs against a second agent.30


Secukinumab immunogenicity was evaluated at baseline and at weeks 12, 24 and 52 in blood samples from a total of 2842 subjects with plaque psoriasis exposed to any dose of secukinumab (the majority receiving 150 or 300mg) in six Phase III studies (four with exposure data for 52 weeks; two with exposure data up


to 12 weeks). ADAs were detected in ten subjects from three studies with 52-week exposure data and were not detected in the remaining studies. ADA rates in subjects receiving secukinumab 300 and 150mg were three of 1410 (0.2%) and seven of 1395 (0.5%), respectively. ADA rate was low and development of ADAs or neutralising antibodies were not associated with loss of secukinumab efficacy or other issues of clinical concern.31


The formation of ADAs with biologics may prevent patients from achieving a full clinical response and contribute to diminished efficacy and drug survival over time. Antibodies against etanercept have no apparent effects on clinical response, whereas antibodies against infliximab or adalimumab have been associated with diminished clinical response.32


ADAs may decrease the


efficacy of biologic drugs by neutralising them or modifying their clearance and may account for hypersensitivity reactions. ADAs specific to one biologic do not carry cross-linking potential with other biologic agents, but cross- immunogenicity has been demonstrated in the case of an infliximab biosimilar,33 as expected.


Data regarding management strategies to counteract ADA formation and their effects in psoriasis patients are limited. Increasing evidence, primarily in the context of rheumatoid arthritis and other chronic inflammatory diseases, suggests that concomitant administration of methotrexate may prevent or diminish the development of ADAs, thereby improving response rates.34


Health economics


Efficacy and safety are the most important factors driving therapeutic choice, but cost considerations are the main determinants of reimbursement and therapeutic algorithms, whether local (Hospital Therapeutics Committees) or depending on centralised Health Technology Assessment agencies, such as the National Institute for Health and Care Excellence.35


Thus, guidance may differ


locally from the European Medicines Agency-approved SPCs, which take into account only the information included in the dossiers submitted at the time of approval and eventually updated. Health economics are the main reason underlying these differences, because from both efficacy and safety perspectives biologics outperform conventional


www.hospitalpharmacyeurope.com


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