sporine. with previous exposure to cyclo- to severeatopic dermatitis even moderate with patients in efficacy trial, dupilumab demonstrated its this year´s meeting. In the CAFÉ one ofthe highlight´s of certainly The late breaker was session Late Breaker MEDIC
read more on PEER-REVIEWED AL PUBLISHER S CONFERENCE REPORT P AGE 3 26th EADV Congress
Editor skills. improvemight further diagnostic intelligence artificial future, the In plays akey role inearly diagnosis. be lifesaving. The dermoscope Detection of early melanoma can Skin Cancer Prof. dr. Peter van de Kerkhof, Radboud University MedicalCentre, The Netherlands read more on 13-17SEPTEMBER2017 • GENEVA •SWITZERLAND P AGE European Academy ofDermatology andVenereology 9 pathwayanother is new fascinating of more than 5 years. The IL-23 period a treatment over efficacy IL17-Blockersshow sustained Psoriasis severe psoriasis. target intreatment ofmoderate to read more on P AGE 13
Contents
Letter from the Editor COLOPHON
3 Late Breakers Editor Prof. dr. Peter van de Kerkhof 3 Dupilumab: highly effective in patients intolerant to cyclosporine Radboud University Medical Centre, The Netherlands 3 Omiganan – a topical treatment acting on the microbiome in AD Advisory Board Dr. Marjolein de Bruin-Weller 4 Femtomolar: a novel way to block IL-17? UMC Utrecht, The Netherlands Dr. Peter Velthuis 4 Serlopitant: an effective central acting itch blocker Erasmus MC Rotterdam, The Netherlands 5 Ixekizumab: also effective in genital psoriasis Dr. Marcel Pasch 6 Tildrakizumab: a novel anti-IL-23 agent for treatment of psoriasis Radboud University Medical Center, The Netherlands 6 Guselkumab safe and effective over two years Prof. Dr. Torello Lotti 7 Ustekinumab: superior drug survival according to a Danish registry University of Rome, Italy Dr. Hessel van der Zee 7 Tyrosine kinase inhibitor effective in pemphigus vulgaris Erasmus MC Rotterdam, The Netherlands 8 Sexually Transmitted Infections 8 A global health challenge Editorial Manager Lisa Colson Editorial Coordinators Nalinee Pathak, MSc. 9 Quadrivalent vaccines offers 100% protection against genital warts Bas Braakman, MSc. 9 Skin Cancer Executive Publisher Rene Draper, MSc. Medical Writer Dr. Susanne Kammerer 9 An Update Production Manager Desiree Heijl 12 Dermatologists: key player in the care of patients with metastatic Graphic Design MOOZ grafisch ontwerp melanoma Lay Out In het Houten Paard 13 Management of Psoriasis All rights reserved. No part of this publication may be reproduced, distributed, or transmitted 13 Many new agents in the pipeline in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of 16 New data on psoriasis comorbidities the publisher, except in the case of brief quotations embodied in critical reviews and certain other noncommercial uses permitted by copyright law. 18 Atopic Dermatitis Copyright ©2017 Medicom Medische Uitgeverij BV 18 The beginning of a new era Disclaimer: 20 JAK inhibitors –new oral treatment options in AD The ideas and opinions expressed in this journal or other associated publications do not necessarily reflect those of Medicom Medical 21 Management of Acne: A Disease with Many Facets Publishers. Although great care has been taken in compiling the content of this publication, Medicom is not responsible or liable in any way for the 21 The right approach for every patient currency of the information, for any errors, omissions or inaccuracies in the original articles, or for any consequences arising from the content. Approved 22 Rosacea: New Perspectives on the Horizon product information should be reviewed before prescribing. The mention of any product, service, or therapy in this publication should not be construed 22 Focusing on the phenotype rather than the subtype as an endorsement of the products mentioned. It is the responsibility of the treating physician or other health care provider, relying on independent 23 Hair Loss in Women experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Readers are advised to check 23 New and adjuvant treatment options the appropriate medical literature and the product information currently 25 provided by the manufacturer of each drug to be administered to verify Treatment of the Aging Face the dosage, method, and duration of administration, or contraindications. 25 Current trends in skin rejuvenation Readers are also encouraged to contact the manufacturer with questions about the features or limitations of any products. Medicom assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the material contained in this publication or to any errors or omissions.
Postal address Head Office Medicom Medical Publishers Medicom Medical Publishers PO Box 90 Faas Eliaslaan 5 Zipcode 3740 AB 3742 AR Baarn City Baarn The Netherlands Country The Netherlands
Telephone +31 85 4012 560 Fax +31 85 4012 569 E-mail [email protected] ISSN 2468-8762 17:17 Letter from the Editor Prof. dr. Peter van de Kerkhof
Dear Reader, Biography Peter van de Kerkhof is It is my great pleasure to present the report on 2017 -EADV Professor in Dermatology and Chairman of the Department Annual meeting held in Geneva on September 13-17. The of Dermatology of the Meeting was a huge success and the programme covered all University Medical Centre aspects of dermatology and venereology, incorporating both St. Radboud, Nijmegen. explorative research and clinical studies. For this report we Professor van de Kerkhof have selected the presentations that may be most interest to graduated in Medicine from the practicing clinicians. We have focused on the late breaker the Catholic University of Nijmegen in 1978 and trained session, STIs, psoriasis management, skin cancer and aesthetic in Dermatology at the Radboud medicines. University Nijmegen Medical Centre, Nijmegen. Since his first We hope that you enjoy our selections. publication on psoriasis in 1980, Professor van de Kerkhof has With best regards, kept a long-standing commitment to research on the pathogenesis and Prof. dr. Peter van de Kerkhof. treatment of psoriasis. He serves as Editor or Associated Editor for 7 dermatological journals and has published over 700 publications in peer-reviewed journals. Professor van de Kerkhof is a member of 12 international dermatology organisations and is past President of the European Society for Dermatological Research, the European Dermatology Forum and the International Psoriasis Council. Late Breakers
As every year, the late breaker session attracted De Bruin-Weller. The mean change improvement in EASI numerous visitors. In this session, new trials from from baseline at 16 weeks (a secondary endpoint) was 78% different dermatologic indications are presented. and 80% in the dupilumab/TCS group, compared to 47% for Enclosed is a selection of most fascinating or possibly those who received placebo plus TCS (P< 0.0001). practice changing studies. Other secondary endpoints of the study included measures of the impact of dupilumab on the persistent itch caused Dupilumab: highly effective in patients by the disease, quality of life measures, and symptoms of intolerant to cyclosporine anxiety and depression. Itch, measured by the mean percent In the Café study, dupilumab with topical corticosteroids improvement of baseline in the pruritus Numerical Rating (TCS) significantly improved measures of overall disease Scale (NRS), was 52% and 54% in the two dupilumab groups, severity, skin clearing, itching, and patient reported quality of compared to 25% for those who received placebo plus TCS life measures [1]. All patients included in the Café trial had (P< 0.0001). an inadequate response to TCS and an Eczema Area and Severity Index (EASI) score of over 20. “Two thirds of our Significant better quality of life patients had been previously treated with cyclosporine, but In the dupilumab groups, 78% and 88% of patients in the could not continue due to side effects and/or inefficacy, so dupilumab groups were able to gain a greater than or equal our participants were really difficult to treat patients”, said Dr. to four-point improvement from baseline in a quality of life Marjolein De Bruin-Weller, Dermatologist, National Expertise questionnaire (Dermatology Life Quality Index), compared to Center for Atopic Dermatitis, University Medical Center 44% of those who received placebo plus TCS (P< 0.0001). Utrecht, Utrecht (Netherlands). No new adverse events were reported in the study. The proportion of patients reporting an adverse event was The primary endpoint of the study was the proportion of similar among the treatment arms. Conjunctivitis was more patients that achieved a 75% or greater improvement in the frequent in patients who received dupilumab with TCS, with EASI score at 16 weeks from baseline. A total of 325 patients 16% and 28%, compared to 11% for patients who received in Europe were randomised into three treatment groups. 59% placebo with TCS. Injection site reactions were reported in of patients who received dupilumab weekly with TCS, and 11% and 4% among patients who received dupilumab with 63% of patients who received dupilumab every two weeks TCS weekly or every two weeks, respectively, compared to with TCS achieved the primary endpoint, compared to 30% 5% for patients who received placebo with TCS. “The CAFÉ of patients who received placebo with TCS (P< 0.0001) in trial shows us that dupilumab can be used in patients who the overall population. In the patients with prior cyclosporine have previously used CsA and stopped it due to intolerance or (CsA) use, 58% of patients who received dupilumab weekly lack of efficacy and who are not candidates for CsA because with TCS, and 57% of patients who received dupilumab of medical conditions or use of contraindicated concomitant every two weeks with TCS achieved the primary endpoint, medications “concluded Dr. de Bruin-Weller. The results in compared to 26% of patients who received placebo with this study are similar to earlier phase 3 studies (16- and 52- TCS (P= 0.0001 for the high dose and P= 0.0002 for the week studies) of dupilumab with or without concomitant TCS. lower dose). “Not only the CsA naïve, but also the patients with prior CsA therapy fared better with dupilumab: the Omiganan – a topical treatment acting on the curves diverged early, already after two weeks of treatment”, microbiome in AD said Dr. De Bruin-Weller. Primary outcome (EASI 75) was A phase II trial shows promising results for omiganan, an comparable to those at week 52 for a CAFÉ-like subgroup antimicrobial peptide for the topical treatment of atopic of patients in the CHRONOS trial (Figure 1). “As we have dermatitis (AD) [2]. Omiganan has anti-inflammatory and 50 weeks treatment data from the CHRONOS trial, we can immune modulatory properties that could be beneficial in superimpose that the efficacy remains long-term”, said Dr. AD. In addition, it is active against gram-positive pathogens
LATE BREAKERS 3 Figure 1: EASI-75 Response in the CAFÉ trial (week 16) and CHRONOS I trial presented by Prof. Fredrik Frejd, Affibody AB, Uppsala CAFÉ like population (week 52). Source: Lecture Dr. De Bruin-Weller. University, Stockholm (Sweden) [3]. So-called Affibody technology was utilised to generate a novel non-antibody EAS Similar in CA Week and C RONOS CA like Population Week affinity protein based trap with high affinity and selectivity 100 to IL-17A, a proinflammatory cytokine that plays a key role 90 in pathogenesis of psoriasis. The molecule with a crystal 80 structure is 25times smaller than an antibody, which allows 70 to give a higher dose in a given injection volume. “Our 62.6* 60 59.1* molecule binds to both sides of IL-17, whereas secukinumab 52.4+ 50.0 50 and ixekizumab only bind to one”; explains Prof. Frejd (Figure 2). The molecule has a very good stability and shows 40 29.6 basically no degradation. Single and multiple injections in 46 30 healthy volunteers were well tolerated. Physiologically, IL- 20 18.6 Patients achieving EASI-75(%) Patients 17 helps to fight fungal infections. “For us it was important 10 do demonstrate that we did not find candidiasis in patients 0 treated with this highly effective molecule”, said Prof. Frejd. In CAFÉ CHRONOS CAFÉ-like addition, efficacy was assessed in 13 patients with moderate to severe plaque psoriasis. In patients with psoriasis, a such as staphylococcus that are abundant on the skin of AD dose-dependent response was demonstrated. Femtomolar patients. The mode of action (MOA) of omiganan is to shift has a half-life of 12 days. Upon subcutaneous injection, the the microbiome of AD patients towards the microbiome seen bioavailability was 75-80%. A dose of 40mg resulted in an in healthy skin. In the dose finding trial, 36 young patients early onset of effect within days after administration, and in with mild to moderate AD were included. A target lesion was a mean PASI reduction of 40% at one week and 60% at three treated either with vehicle or with omiganan in two doses weeks after administration. Initial results of repeated dosing (2.5% and 1%). Patients had to rate their itch by an app. In resulted in a higher reduction of absolute PASI compared to addition, the app reminded to apply the ointment. Primary a single administration. endpoint of this trial was the effect in the Scoring Atopic A phase II trial will be initiated in the next weeks. Dermatitis (SCORAD) Index. Prof. Robert Rissmann, Centre for Human Drug Research, Leiden (The Netherlands) pointed Serlopitant: an effective central acting itch out, omiganan 2.5% was more effective than placebo: In blocker addition, the microbiome in the target lesion was assessed. Chronic pruritus is a disorder with multiple aetiologies. It can In the high omiganan dosing group, staphylococcus species lead to sleep impairment, depression, and anxiety. It has a were significantly reduced compared to baseline. “Therefore, major impact on quality of life [4]. we could proof that omiganan is really acting by a shift in the microbiome from lesional to a non-lesional profile”, said “Patients would like to forfeit on average 13% of their lifespan Dr. Rissmann. As this was the first study with omiganan, it to live without this condition”, said Dr. Paul, Kwon, Menlo was tested on a single lesion. Now a trial with a whole-body Therapeutics Inc, Menlo Park, California (CA/USA). Therefore, application is planned. In vitro, omiganan shows efficacy medication that offers a rapid resolve of pruritus is required against staphylococcus aureus, which hints to a direct effect in different indications in dermatology. Stimulation of the of the agent. tachykinin neurokinin 1 receptor (NK1-R) is an important “Adherence in this trial was extraordinarily high (98.3% of pathway for pruritus perception. This receptor is expressed participants). Also, this trial shows that an app can be a on multiple cell types throughout the body. Serlopitant is a helpful tool to ensure compliance, at least in young patients, small-molecule, that is a highly potent and selective NK1-R said Prof. Rissmann. antagonist. Disrupting the itch signal by NK1-R antagonism has been shown to reduce the intensity of itch in chronic Femtomolar: a novel way to block IL-17? pruritus [5]. Serlopitant has demonstrated to affect the central Femtomolar may still be a long way off clinical application, nervous system and manifests a binding of more than 90% but the molecule is strikingly effective according to a phase of the NK1-R. Signaling on the nerve axis is an important part
4 CONFERENCE REPORT - EADV 2017 Figure 2: Femtomolar has a crystal structure and is able to completely capture the IL-17A/A the 5-mg dose, compared with placebo. homodimer. Source: Lecture Dr. Frejd. The initial improvement in pruritus was sustained to week 6 in both dosing groups. Chrystal Structure of IL- A and Bi-specific ligand trap completely IL- A binding Affibody molecule captures IL- A/A homodimer Almost all side effects were mild or moderate although they occurred more frequently with serlopitant. The percentage change from baseline Visual Analogue Scale itch score was significantly greater with serlopitant 1mg (-41,4; P= 0,022) and 5 mg (-42,5; P= 0,013) at week 6 compared with placebo (-28,3).
Ixekizumab: also effective in Albumin genital psoriasis binding molecule Although genital psoriasis is common (up to 60%) in patients with plaque psoriasis, there IL- A binding Affibody molecule Very high affinity (KD) . pM exists only limited data from clinical trials Small size (M ) . kD [6]. “We have so many trials with systemic biologics, but no trial has addressed genital of the itch process. “You feel no itch before this feeling is not psoriasis up to know, so we hope that this trial will create processed to the neuron”, explained Dr. Kwon. more awareness of this problem”, said Prof. Caytriona Ryan, St. Vincent´s Hospital, Dublin (Ireland), at the presentation of In the Phase II TCP-101 study 3 doses of serlopitant were the trial [7]. tested against placebo in 257 patients that suffered from All included patients failed to respond or were intolerant of pruritus that lasted at least 6 weeks and was nonresponsive or at least one topical therapy for genital psoriasis. In addition, inadequately responsive to topical steroids or antihistamines. they had to have plaque psoriasis in a non-genital area. Patients were treated for six weeks. Serlopitant provided Patients needed only to have a Body Surface Area (BSA) ≥ 1% a statistically significant improvement in chronic pruritus, in this trial, although usually psoriasis patients do not qualify beginning as early as day 2 with the 1 mg dose and day 3 with for systemic treatment, if they have less than 10% BSA. “I think to include these patients was very important, because Figure 3: Primary endpoint of the trial: sPGA of genitalia (0,1) quality of life is so much more impaired if plaques are located response rate. Source: Lecture Prof. Ryan. in this region”, said Prof. Ryan.
PBO (N=74) IXE Q2W (N=75) 100 The primary endpoint was a Physician Global Assessment (PGA) of 0 or 1 in the genital area, which means clear or almost 80 73† clear skin. After 12 weeks of treatment, 73% of the treatment † group reached this primary endpoint (P< 0.001 vs. placebo), 60 † an effect could already be seen after one week (Figure 3). In addition, ixekizumab was effective in a couple of secondary
40 † endpoints. Genital itch, that was assessed in patients that Response (%) Response had at least an itch of 3 and more at baseline in a numerical * rating scale (NRS), improved also by 60%. “For me the most 20 8 important result is that 78% of patients, whose genital disease affected sex life in the beginning were not disturbed anymore 0 0 1 2 4 6 8 10 12 at week 12, and a significant improvement was evident as Week early as one week after baseline”, said Prof. Ryan. *P<.01 vs. PBO; † p<.001 vs. PBO ITT= Intent-to-treat; IXE Q2W=80mg ixekizumab every 2 weeks; NRI=non-responder imputation; Safety outcomes were consistent with the overall safety PBO=placebo; sPGA=static Physician’s Global assessment profile of ixekizumab.
LATE BREAKERS 5 Tildrakizumab: a novel anti-IL-23 agent for IL-23 blockers have the clinical advantage that they have to treatment of psoriasis be dosed less frequently. After guselkumab, tildrakizumab is The investigational highly selective IL-23 inhibitor likely to become the second IL-23 inhibitor to be approved by tildrakizumab appears to be effective for the treatment the FDA. of psoriasis over a treatment period of two years: These encouraging results showed long-term extensions of Guselkumab safe and effective over two years two phase 3 trials: reSURFACE1 and reSURFACE2 [8]. All The phase III VOYAGE-1-trial was designed to evaluate participants in the extension studies had achieved at least the efficacy and safety of the IL-23 inhibitor guselkumab PASI 50 in the original studies and the treatment that was compared with placebo and adalimumab in adults with given at the end of the study was continued open label. 474 moderate to severe plaque psoriasis. Patients received patients completed the extension study reSURFACE1 and 100 mg guselkumab at weeks 0 and 4, then every 8 weeks. 688 patients completed the extension study of reSURFACE Participants that completed the randomised, double-blind 2. More than 80% of patients treated with tildrakizumab 200 VOYAGE-1-trial were able to enter the extension trial. “Today mg for 2 years achieved a 75% reduction in Psoriasis Area I can present you the two-year data from the open label Severity Index score (PASI 75), and adverse event rates were extension of the VOYAGE 1 trial”, said Dr. Andrew Blauvelt, low. Oregon Medical Research Center, Portland (OR/USA) [9]. "Over two years, we have a minimal decline in PASI levels in both study populations," said investigator Prof. Kim Papp, “We see very high PASI responses regardless of whether Probity Medical Research in Waterloo (Canada). patients have been on guselkumab from the beginning, or After 2 years, 30% of patients had clear skin (PASI 100). “There started with placebo or adalimumab in the first year and was a slight decline, but again, it was only minimal over two were then switched to guselkumab – those patients did just years”, said Prof. Papp. as well”, said Dr. Blauvelt. PASI 75 response at 100 weeks Adverse events, including severe infections and malignancies, were between 94.8% and 97.5%. There was a remarkable will be monitored for about 5 years, but rates were low for low drop-out rate of only 2-6% in the second year. After 100 both doses at 2 years, and there were no deaths. weeks, 96.8% of patients reached a PASI 75 response, 83.8%
Figure 4: Proportion of patients who achieved PASI 75, PASI 90, PASI 100, IGA Score of 0/1, IGA Score of 0 (week 0-100), as observed. Source: Lecture Dr. Blauvelt.