Expert Opinion on Biological Therapy

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Adalimumab for treating childhood plaque psoriasis: a clinical trial evaluation Vito Di Lernia To cite this article: Vito Di Lernia (2017): Adalimumab for treating childhood plaque psoriasis: a clinical trial evaluation, Expert Opinion on Biological Therapy, DOI: 10.1080/14712598.2017.1369950 To link to this article: http://dx.doi.org/10.1080/14712598.2017.1369950

Published online: 22 Aug 2017.

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Date: 23 August 2017, At: 16:44

EXPERT OPINION ON BIOLOGICAL THERAPY, 2017 https://doi.org/10.1080/14712598.2017.1369950

CLINICAL TRIAL EVALUATION

Adalimumab for treating childhood plaque psoriasis: a clinical trial evaluation Vito Di Lernia Dermatology Unit, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy ARTICLE HISTORY

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ABSTRACT

Introduction: Most systemic therapies have not been systematically investigated in moderate to severe childhood plaque psoriasis. Evidence on the efficacy and safety of systemic treatments is limited and therapeutic guidelines are lacking. Recently adalimumab, a fully human monoclonal antibody that binds tumor necrosis factor (TNF)- alpha, was investigated in childhood psoriasis. Adalimumab is licensed for many inflammatory conditions including chronic plaque psoriasis in adults. Areas covered: A randomized phase III study published provided favourable efficacy and safety data of adalimumab in childhood psoriasis. The active comparator was methotrexate. After 16 weeks of treatment, a PASI 75 score was achieved in 58% of patients within the adalimumab 0.8 mg/kg group compared with 32% of patients within the methotrexate group. Safety data gave no evidence of drug-related serious adverse events and no organ toxicity. This is the first randomised controlled study of either adalimumab or methotrexate in children and adolescents with psoriasis. Expert opinion: The aforementioned trial was the first to provide clinical data on adalimumab’s efficacy and safety in the short term when treating children and adolescents with psoriasis. Through the use of an active comparator, this study has opened the way for the future assessment of systemic therapies in children and adolescent with this condition.

1. Introduction Adalimumab is a recombinant, fully human immunoglobulin (IgG1) monoclonal antibody that binds to the soluble and transmembrane forms of tumor necrosis factor (TNF)-α and inhibits the binding of TNF-α to its receptors [1,2]. It is licensed for many inflammatory conditions, including plaque psoriasis, psoriatic arthritis, rheumatoid arthritis, axial spondyloarthritis, Crohn’s disease, ulcerative colitis, polyarticular juvenile idiopathic arthritis, active enthesitis-related arthritis, hidradenitis suppurativa and non-infectious uveitis [3]. In childhood, most patients present with mild psoriasis. Topical corticosteroids are presently the mainstay of therapy. Nevertheless, moderate or severe forms of the disease may be refractory to or unmanageable with topical therapy and need more aggressive approaches, as phototherapy and systemic drugs. Although psoriasis is primarily a disorder of the skin, there is increasing evidence that the disease has multiple comorbidities, even in children [4–6]. The availability of innovative and effective drugs represents a significant step forward in the treatment of childhood psoriasis. Indeed, for the most part, systemic therapies have not been thoroughly investigated in children. Available data about conventional drugs are limited to case series [5,7–9]. Therefore, beneficial effects of therapies have been assumed because of clinical evidence and experience in adults [5,10]. Consequently, a considerable variation in the choice of the first-line systemic therapy is detected [11]. Finally, there is a substantial unmet need for treatment options in children and adolescents recalcitrant to topical therapy or phototherapy. As understanding of the role of proinflammatory signaling molecules in the psoriatic disease process has grown, CONTACT Vito Di Lernia

[email protected]

© 2017 Informa UK Limited, trading as Taylor & Francis Group

Received 10 June 2017 Accepted 17 August 2017 KEYWORDS

Childhood; adolescence; psoriasis; treatment; adalimumab; TNF

several biologic agents have been engineered to target key cytokines associated with immunopathogenic pathways. They included initially TNF-α, then interleukin (IL)-12 and IL-23, and more recently IL-17, but only in adult patients [12]. Etanercept was the first biological licensed for the treatment of chronic severe plaque psoriasis in children aged ≥6 years in Europe and ≥4 years in USA. Adalimumab received approval in 2015 by European Medicines Agency for the treatment of severe chronic plaque psoriasis in children and adolescents aged ≥4 years of age who have had an inadequate response to or are inappropriate candidates for topical therapy and phototherapies. Therefore, it is now a first-line systemic treatment. The goal of this article is to review the efficacy and safety data from the clinical trial on the use of adalimumab in childhood psoriasis [13] [ClinicalTrials.gov number NCT01251614] and to provide expert insight regarding future studies (Box 1).

2. Study design This double-blind, phase III trial was conducted in 13 countries, 9 of which European. A total of 114 patients were randomized to either adalimumab 0.8 mg/kg (up to 40 mg total dose) or 0.4 mg/ kg subcutaneously at week 0, then every other week starting at week 1, or oral methotrexate once weekly (0.1–0.4 mg/kg) up to 25 mg per week for 16 weeks. Patients aged ≥4 to 10 or PASI > 10 and DLQI > 10. The active comparator was methotrexate. Of note, methotrexate was selected as the most nominated gold standard amongst systemic agents in this regard [15]. In addition, methotrexate was suggested as the traditional systemic treatment of choice in children with severe, recalcitrant plaque psoriasis [16]. Therefore, the choice of the active comparator is adequate. About outcome measures, the PGA is a valid and reliable measure of psoriasis severity frequently used in clinical trials as an efficacy end point. Extensively used is also the PASI, which combines the assessment of the severity of lesions with the body

3. Key results 3.1. Demographics The treatment groups were similar in demographic and disease characteristics at baseline, although slightly more patients in the adalimumab 0.8 mg/kg group had been previously treated with systemic and biological therapies. All patients (n = 6) age 4–6 years were allocated to the adalimumab 0.4 mg/kg group. Median PASI score was 17.5 (methotrexate group), 15.6 (adalimumab 0.4 mg/kg group), 15.3 (adalimumab 0.8 mg/kg group).

3.2. Primary endpoints At 16 weeks, a PASI 75 response was achieved in 58% of patients in the adalimumab 0.8 mg/kg group and in 32% of those in the methotrexate group (p = 0.027) (non-responder imputation). PASI 75 response to adalimumab was rapid with a significant difference compared with methotrexate reached by week 4 (p = 0.002). At week 16, percentage of patients that achieved clear or minimal PGA score was 61% in the adalimumab and 41% in the methotrexate group (p = 0.083). Consequently, the difference did not reach significance.

3.3. Secondary efficacy outcomes Adalimumab provided clinical benefits in terms of secondary end points, with a higher proportion of patients in the adalimumab group achieving a PASI 90 (29% versus 22%) and PASI 100 responses (18% versus 3%). This difference between adalimumab and methotrexate groups in the second primary end points was not statistically significant. Responses to adalimumab were lost following treatment withdrawal, but largely recovered during retreatment with adalimumab. Efficacy was maintained through the additional open label extension 52 weeks of adalimumab treatment.

3.4. Quality of life outcomes The mean decrease (improvement) in CDLQI score from baseline was numerically, but not significantly, higher in patients in the adalimumab group.

EXPERT OPINION ON BIOLOGICAL THERAPY

3.5. Safety Adverse event profiles were similar between groups. The most commonly reported adverse events in patients were infections. Injection site reactions occurred in 11% of patients in the adalimumab 0.8 mg/kg group and in 8% of patients in the methotrexate group. In the initial treatment period, no patient discontinued treatment because of an adverse event. Adalimumab showed a similar safety profile to methotrexate over the double-blind controlled period. No drug-related serious infections were reported during the 52-weeks open label period, as well as no malignancies and no deaths have been observed.

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severe psoriasis warranting systemic therapy is limited. And, in fact, in this study, 114 patients were enrolled in as many as 38 clinics. We agree with Rose and Happle [23] that Psoriasis Pediatric Investigation trials may raise logistic barriers in the enrolment of patients. In particular, the group of patients with BSA affected more than 20%, PASI score more than 20 is outnumbered. About childhood psoriasis, there is little point in separating moderate-to-severe disease from severe disease. Therefore, an accurate choice of the study design, inclusion criteria, and appropriate severity cut-off points should be carefully thought trough in future psoriasis pediatric trials.

Funding

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4. Expert opinion Pediatric and adolescence psoriasis has a great impact on the psychological health of patients and patients’ families [18]. Presently, psoriasis is treated in a stepwise fashion based on the severity, extension, and degree of involvement with more severe and extensive disease warranting systemic treatments. But, unlike adults, the absence of approved systemic therapies has complicated management of psoriasis in children and adolescents. The lack of randomized controlled trials in childhood has been the major gap in the required knowledge for drug efficacy and safety to draw up standardized therapy guidelines. Etanercept, an inhibitor of TNF-α, was the first drug investigated in a randomized controlled trial versus placebo for the treatment of children and adolescents with psoriasis [19]. An open-label extension study for patients enrolled in the aforementioned study showed that rates of PASI and static PGA remained relatively stable with long-term treatment with etanercept. In addition, no new safety concerns were raised [20]. Etanercept was effective in maintaining remission at 52 weeks in a real-life cohort of children and adolescents with moderate-to-severe plaque psoriasis [21]. The present study on adalimumab confirms that targeting the TNF-α may result in a significant improvement of psoriasis not only in adults, but also in younger patients. It is worth noting that this is the first head-tohead study in pediatric psoriasis. In the short term, adalimumab provided greater efficacy than methotrexate with a similar safety profile. Indeed, a PASI 75 response achieved in 58% of patients treated with adalimumab represents a substantial reduction in disease severity. It is comparable to that achieved by etanercept at week 12 in placebo-controlled trial by Paller et al. [19]. However in etanercept trial, patients had a baseline PASI score of at least 12, and therefore lower. Papp et al. hypothesized that the lack of significance in PGA responses between adalimumab and methotrexate group might have been caused by the limited sample size and power of the study [13]. No new safety risks were identified, although longer observations are mandatory to assess the safety in children. However, because of more extensive experience with its use in juvenile idiopathic arthritis, adalimumab has gathered a valuable body of safety evidence [22]. Through the use of an active comparator, this study has opened the way for future assessment of systemic therapies in children and adolescent with psoriasis. Given the relatively small sample size, it is challenging to weigh the magnitude of its results. A different design, with only two groups of patients, one on adalimumab and one on methotrexate, could have obtained more significant results. It has to be said that the population of children, especially before adolescence, with

This manuscript has not been funded.

Declaration of interest V Di Lernia was a principal investigator for clinical studies sponsored by Sanofi, Regeneron and Coherus as well as in observational studies sponsored by AbbVie. He was also an advisory board member for AbbVie. He has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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19. Paller AS, Siegfried EC, Langley RG, et al. Etanercept treatment for children and adolescents with plaque psoriasis. N Engl J Med. 2008;358:241–251. •• The first randomized controlled trial on use of etanercept versus placebo in pediatric psoriasis. 20. Paller AS, Siegfried EC, Pariser DM, et al. Long-term safety and efficacy of etanercept in children and adolescents with plaque psoriasis. J Am Acad Dermatol. 2016;74:280–287. 21. Di Lernia V, Guarneri C, Stingeni L, et al. Effectiveness of etanercept in children with plaque psoriasis in real practice: a one-year multicentre retrospective study. J Dermatolog Treat. 2017 Aug 18:1-3. • A retrospective real-life study on short and long-term effectiveness of etanercept in pediatric psoriasis. 22. Klotsche J, Niewerth M, Haas JP, et al. Long-term safety of etanercept and adalimumab compared to methotrexate in patients with juvenile idiopathic arthritis (JIA). Ann Rheum Dis. 2016;75:855–861. 23. Rose K, Happle R. The effect of regulation on pediatric psoriasis drug approvals: the challenge of the european union pediatric investigation plans. Pediatr Dermatol. 2017;34:e154–9. • Viewpoints and perspectives about the randomized clinical trials on pediatric psoriasis.

Adalimumab for treating childhood plaque psoriasis: a clinical trial evaluation.

Most systemic therapies have not been systematically investigated in moderate to severe childhood plaque psoriasis. Evidence on the efficacy and safet...
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