Infliximab for psoriasis

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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

                                                                                          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.
                                                                                          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
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
                                                                                          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


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:
     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                  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         
     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