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New Medicines Profile December 2005 Issue No. 05/15 Infliximab for psoriasis Concise evaluated information to support the managed entry of new medicines in the NHS Introduction Summary Infliximab inhibits tumour necrosis factor • Infliximab inhibits tumour necrosis factor α, a pro-inflammatory cytokine (TNF) α, a pro-inflammatory cytokine implicated in the pathogenesis of psoriasis. implicated in the pathogenesis of psoriasis • Two relatively large trials primarily designed to investigate the efficacy of for which it has recently received a licence infliximab in plaque psoriasis have been conducted. In the longest phase III extension. Infliximab is also licensed for trial (‘EXPRESS’) infliximab was administered at a dose of 5mg/kg at weeks use in rheumatoid arthritis, Crohn's 0, 2, and 6, then every 8 weeks to week 46. At week 10, 80% of patients disease, ankylosing spondylitis and treated with infliximab achieved a PASI (Psoriasis Area and Severity Index ) psoriatic arthritis. It is the second TNF α 75, and 57% achieved a PASI 90, compared with 3% and 1% in the antagonist licensed for psoriasis, the other placebo group, respectively (P<0·0001). However at week 50, PASI 75 and being etanercept. Efalizumab, another PASI 90 fell to 61% and 45% respectively. The proportion of patients ‘biologic’ therapy, is also available for the achieving a PGA score of clear or minimal with infliximab was 83% at week treatment of psoriasis. There is no 10, however this had fallen to 53% at week 50. international consensus on the best efficacy measure for psoriasis studies, • The main adverse events reported included a number of those already although the European Medicines listed in the Remicade SPC, e.g. infusion-related reactions and antibody Evaluation Agency recommend two formation. However in EXPRESS there were 3 reports of skin malignancies endpoints should be used to assess in the infliximab group. efficacy: a validated, standardised global • Imminent NICE guidance on the related ‘biologic’ therapies etanercept and score (e.g. physician’s global assessment efalizumab for psoriasis specifies starting and stopping criteria for these [PGA]) in conjunction with the Psoriasis therapies. Infliximab is not included in this guidance, however it is the most Area and Severity Index (PASI).1 It is extensively used ‘biologic’ in dermatological practice. There are no direct considered that PASI alone is not sufficient comparative studies, yet an evidence synthesis of the available data found to evaluate psoriasis severity at baseline that infliximab was more effective than both efalizumab and etanercept (25 and on treatment. mg dose). Mode and duration of administration are other factors to be taken into consideration when choosing between therapies. Evidence There are data on the effect of infliximab • At present, the risks and benefits of ‘biologic’ therapies, relative to the on psoriasis from eligible patients in much cheaper conventional systemic therapies, are unknown. Therefore psoriatic arthritis trials, however this early use of these agents is inappropriate and is not supported by their monograph will only consider trials licensed indications. primarily designed to investigate plaque psoriasis. Brand Name, (Manufacturer): Remicade, (Schering-Plough) A double-blind phase II trial (SPIRIT) BNF Therapeutic Class: 13.5.3 Drugs affecting the immune response randomised 249 patients in a 2:2:1 ratio to infliximab 3mg/kg, 5mg/kg or placebo, New Licensed Indication: Treatment of moderate to severe plaque psoriasis administered at weeks 0, 2 and 6.2 in adults who failed to respond to, or who have a contraindication to, or are Subjects had a diagnosis of plaque intolerant to other systemic therapy including ciclosporin, methotrexate or psoriasis for at least six months, and had PUVA. previously been treated with PUVA or other Dosage and Administration: 5 mg/kg given as an intravenous infusion over systemic antipsoriasis treatments. Patients a 2-hour period followed by additional 5 mg/kg infusion doses at 2 and 6 with a baseline PASI score of 12 or more weeks after the first infusion, then every 8 weeks thereafter. If a patient shows and psoriatic plaques covering at least no response after 14 weeks (i.e. after 4 doses), no additional treatment with 10% of their body surface area were infliximab should be given. eligible for randomisation. Median baseline Marketed: September 2005 PASI scores were 20, 20 and 18, and Cost Comparisons: [Prices from MIMS – October 2005. VAT added] median body surface area involvement was 29%, 25% and 26% for the 3mg/kg, Drug Usual dose range Approximate annual cost 5mg/kg and placebo groups, respectively. £15,800 for the first year and The primary endpoint was the proportion of Infliximab As above patients achieving a >75% improvement in £12,800 thereafter† PASI from baseline (PASI 75) at week 10. Etanercept 25 mg administered twice weekly £5000 - £11,000§ The effect of infliximab treatment on An initial single dose of 0.7 mg/kg patient QoL was also assessed. Patients Efalizumab followed by weekly injections of £10,300* were followed up to week 26 to assess 1.0 mg/kg duration of response and those with a PGA † For a typical 70kg patient of moderate to severe at week 26 were § There are no stipulations as to the period needed to be allowed between successive eligible for an additional infusion of their treatment episodes. Expert advice shows that people who had responded to etanercept assigned study treatment. At week 10, sometimes relapsed within weeks of therapy cessation and in practice intermittent and 72% of the 3mg/kg group and 88% of the continuous therapy frequently converged. Therefore the costs quoted above are likely to 5mg/kg group had reached the primary be the extremes and the annual cost for most patients would lie somewhere in between. *For patients up to 100kg. endpoint, compared with 6% of the placebo group (P<0.001). Also, a N.B. Doses shown for general comparison and do not imply therapeutic equivalence significantly greater proportion of patients Infliximab for psoriasis treated with infliximab had PGA scores significant difference in PASI 50 recorded cancer, which possibly becomes more rating symptoms as minimal or cleared between the two groups (P<0·0001). At relevant in psoriasis patients who have compared to placebo (P<0.001). Median week 6, significantly more infliximab been previously treated with baseline Dermatology Life Quality Index patients than placebo patients achieved phototherapy7 and/or immuno- (DLQI) scores were 11, 12 and 14 for the PASI 75 and PASI 90 (P<0·0001). No suppressant drugs.8 3mg/kg, 5mg/kg and placebo groups, DLQI data were presented in this study. These data come from relatively short respectively. The median change from There was evidence that loss of clinical trials (the majority of EXPRESS safety baseline in DLQI to week 10 in the response was related to low infliximab data were only up to 24 weeks), so the 3mg/kg and 5mg/kg groups were -8 and serum concentrations and/or a positive long-term AE profile of infliximab in this -10, respectively, compared with a infliximab antibody status. It was patient group has not been assessed in median change of zero in the placebo suggested that a subgroup of patients full. group (P<0.001). A separate analysis of may require more frequent Place in Therapy these DLQI results has also been administration to maintain response, published.3 At present, the long-term risks and although this has obvious financial benefits of ‘biologic’ therapies, relative A phase III, multicentre, double-blind implications. However, an abstract of a to the much cheaper conventional trial (EXPRESS), randomised 378 patients recently completed trial (EXPRESS II; systemic therapies are unknown. in a 4:1 ratio to infliximab 5 mg/kg or n=835) comparing regular vs. on Therefore early use of these agents is placebo, administered at weeks 0, 2, and demand maintenance regimens of inappropriate and is not supported by 6, then every 8 weeks to week 46.4 At infliximab reported that a more sustained their licensed indications. week 24, placebo-treated patients improvement in PASI was observed with crossed over to infliximab treatment. regular maintenance doses (P<0.001), NICE guidance on etanercept and Subjects had a diagnosis of moderate-to- although both regimens were efficacious.5 efalizumab for psoriasis is due in severe plaque psoriasis for at least six January 2006. The final appraisal months, were candidates for Safety determination specifies criteria for phototherapy or systemic therapy, had a In both studies more patients receiving patient selection in line with their PASI score of at least 12, and had at infliximab reported serious adverse licensed indications, along with least 10% of their body surface area events (AE) than placebo (6.1% vs. 0% restrictions relating to baseline PASI affected by psoriasis. In both groups the in SPIRIT, and 6% vs. 3% in and DLQI scores, and advice on median baseline PASI score was about EXPRESS).2,4 In the SPIRIT trial infusion- discontinuing therapy.9 Efalizumab is 23, the median body surface area related reactions occurred in a higher only recommended where patients involvement was about 34%, and the nail percentage of infliximab treated patients have failed to respond to etanercept. psoriasis severity index (NAPSI) was (20% vs. 2% for placebo), of which 2 Infliximab is not included in this about 4.5. The primary endpoint was the were scored as severe. In EXPRESS, data guidance, however it is currently the proportion of patients achieving PASI 75 were presented as a percentage of the most extensively used ‘biologic’ in at week 10. Analysis was on an intention- total number of infusions (similar in the dermatological clinical practice.10 to-treat-basis (ITT), as were the two groups at week 24), so it could not Whilst there are no direct comparative secondary endpoints of PASI 50 and PASI be determined what percentage of studies between these agents, the 90 at week 10. Prespecified, non-ITT patients had infusion related reactions. NICE guidance assessment group analyses were used for the further Four serious infusion reactions were conducted an evidence synthesis of the endpoints, including PASI 50, 75, and 90 reported in infliximab-treated patients at available data and found that both at weeks 24 and 50, the proportion of week 50. Infusion reactions occurred efalizumab and etanercept (25 mg patients achieving a PGA score of cleared more frequently when infliximab was dose) were less effective than or minimal at week 10, 24 and 50, and given on a as required basis compared to infliximab.9 This finding is echoed in the percentage improvement from regular infusions.5 Antibodies to recent British Association of baseline in NAPSI at weeks 10, 24, and infliximab were seen in 23% of infliximab Dermatologists guidelines.10 50. A post hoc per protocol analysis was treated patients at week 26 in SPIRIT, As well as the 2-hour infusion time for also conducted. and 22% at week 46 in EXPRESS. In infliximab, patients need to be At week 10, 80% of patients treated with SPIRIT a greater proportion of antibody monitored for at least a further hour infliximab achieved PASI 75, and 57% positive patients experienced an infusion post infusion,6 whereas etanercept is achieved PASI 90, compared with 3% reaction on retreatment compared to given as a subcutaneous injection. and 1% in the placebo group, antibody negative patients (23% vs. Data to date for infliximab show a loss respectively (P<0·0001). At week 24 8%). Although no such data were of response between week 24 and 50. these numbers were maintained, PASI 75 provided in EXPRESS, the SPC for It is not known if this loss of efficacy (82% for infliximab vs. 4% for placebo) Remicade states that patients who will be progressive with longer term and PASI 90 (58% vs. 1%) (P<0·0001). developed antibodies to infliximab were use, so guidelines need to be in place However at week 50, the proportion more likely (approximately 2-3 fold) to to ensure appropriate discontinuation. achieving PASI 75 and PASI 90 fell to develop infusion-related reactions.6 61% and 45% respectively. The However the use of concomitant Key Papers proportion of patients achieving a PGA immunosuppressant agents may reduce 2. Gottlieb AB, Evans R, Li S et al. J Am score of clear or minimal with infliximab the frequency of these reactions,6 and Acad Dermatol 2004;51:534-542 was 83% at week 10, (P<0·0001), anecdotally some clinicians are 4. Reich K, Nestle FO, Papp K, t al. however this had fallen to 53% at week prescribing methotrexate with infliximab Lancet 2005;366:1367-74 50. The percentage improvement from in an attempt to reduce antibody baseline in NAPSI was significantly formation. In both trials more infliximab patients experienced abnormal LFTs. Appendix I: Bibliography greater than placebo at week 10, continued to improve between weeks 10 Three patients had skin malignancies in Adapted from the “On the Horizon- and 24, and was maintained at week 50. the EXPRESS trial. It is important to note Future Medicines” produced by a A therapeutic response to infliximab was that there is a theoretical risk that TNFα collaboration between the NPC and seen as early as week 2, with a antagonists may increase the risk of skin Wessex Drug & Medicines Information Produced for the UK Medicines Information Service by Jonathan Hall, Wessex Drug & Medicines Information Centre, Southampton. Tel 023 8079 6908 The information contained in this document will be superseded in due course. Not to be used for commercial purposes. May be copied for use within the NHS. Infliximab for psoriasis Appendix I Bibliography References 1. Committee for Medicinal Products for Human use 6. Schering Plough Ltd. Remicade: Summary of Product (CHMP). Guideline on clinical investigation of Characteristics, dated 29th September 2005. medicinal products indicated for the treatment of Available from URL: http://www.medicines.org.uk. psoriasis. CHMP/EWP/2454/02corr. EMEA (London), Accessed 02.11.05 November 2004. Available at URL: 7. Esser AC, Abril A, Fayne S et al. Acute development http://www.emea.eu.int/pdfs/human/ewp/245402en of multiple keratoacanthomas and squamous cell .pdf. Accessed 02.11.05 carcinomas after treatment with infliximab. J Am 2. Gottlieb AB, Evans R, Li S et al. Infliximab induction Acad Dermatol 2004;50:S75-S77 therapy for patients with severe plaque-type 8. Davison SC, Bunker CB, Basarab T. Etanercept for psoriasis: a randomized, double-blind, placebo- severe psoriasis and psoriatic arthritis: observations controlled trial. J Am Acad Dermatol 2004;51:534- on combination therapy (letter). Br J Dermatol 542 2002;147:831-32 3. Feldman SR, Gordon KB, Bala M, et al. Infliximab 9. National Institute for Health & Clinical Excellence. treatment results in significant improvement in the Technology Appraisal : Psoriasis - Efalizumab and quality of life of patients with severe psoriasis: a etanercept for the treatment of adults with psoriasis. double-blind placebo-controlled trial. Br J Dermatol Final Appraisal Determination, dated 23rd September 2005;152:954-60 2005 . Available at URL: 4. Reich K, Nestle FO, Papp K, et al. Infliximab http://www.nice.org.uk/pdf/FAD_Psoriasis_Psoriasis induction and maintenance therapy for moderate-to- %20FAD%20for%20consultation%2023%2009%200 severe psoriasis: a phase III, multicentre, double- 5%20(final).pdf. Accessed on 02.11.05 blind trial. Lancet 2005;366:1367-74 10. Smith CH, Anstey AV, Barker JNWN, et al. British 5. Gottlieb AB, Feldman S, Weinstein G, et al. Association of Dermatologists guidelines for use of Infliximab phase III results: every 8 week versus as biological interventions in psoriasis 2005. Br J needed maintenance therapy. Poster of abstract Dermatol 2005;153:486-97 presented at 14th European Academy of Dermatology and Venereology (EADV) annual congress, October 2005, London
"Infliximab for psoriasis"