PracticeUpdate Conference Series World Congress of Dermatology 2019

ISSN 2208-150X (Print) ISSN 2208-1518 (Online)

24 TH WORLD CONGRESS OF DERMATOLOGY 10–15 JUNE 2019 • MILAN, ITALY

THE BEST OF WCD 2019 Expert Outlines Nonsurgical Options for Diffuse Epidermal Field Cancerization • Role of Gut/Cutaneous Dysbiosis in Dermatological Disease Highlighted • Two-Year Study Confirms Long-Term Benefits of Risankizumab in Psoriasis • Topical Ruxolitinib Shows Promise in Relieving Vitiligo Lesions

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CONTENTS WCD 2019 • 10–15 June 2019 • Milan, Italy BY THE PRACTICEUPDATE EDITORIAL TEAM

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3 Expert Outlines Nonsurgical Options for Diffuse Epidermal Field Cancerization 4 Role of Gut/Cutaneous Dysbiosis in Dermatological Disease Highlighted 5 In-Vivo Confocal Microscopy Offers Diagnostic Benefits For Suspected Melanoma 6 Psoriatic Arthritis Expert Implores Dermatologists to Become More Involved in This Condition 8 Two-Year Study Confirms Long-Term Benefits of Risankizumab in Psoriasis 9 Oral Baricitinib Relieved Symptoms of Atopic Dermatitis In Two Phase III Trials

10 Perils of Private-Equity Dermatology Practices Many and Far-Reaching 12 Treatment History May Affect Effectiveness of Some Systemic Therapies for Psoriasis 12 Topical Ruxolitinib Shows Promise in Relieving Vitiligo Lesions 14 Experimental Topical Tropomyosin Receptor Kinase A Inhibitor Improved Psoriasis Severity 15 Extracorporeal Photopheresis With 5-Aminolevulinic Acid Proves Safe in Early Pilot Study

16 Real-World Data Demonstrate 17 Dupilumab Offers Clinically Meaningful Benefit for Adolescent Atopic Dermatitis 18 Xolma Study Suggests Omalizumab May Play Role in Treatment of Cutaneous Mastocytosis 19 Systemic Psoriasis Treatments Equally Effective in Older and Younger Patients 20 Guselkumab Durably Effective in Psoriasis Patients After 3-Year Follow-Up Apremilast Reduces Psoriasis Disease Severity

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WCD 2019 • PRACTICEUPDATE CONFERENCE SERIES

PRACTICEUPDATE DERMATOLOGY BOARD PracticeUpdate is guided by a world-renowned Editorial and Advisory Board that represents community practitioners and academic specialists with cross-disciplinary expertise.

Editor-in-Chief

Robert T. Brodell MD, FAAD Professor and Chair, Department of Dermatology, and Professor of Pathology, University of Mississippi Medical Center, Jackson, Mississippi; Instructor in Dermatology, University of Rochester School of Medicine and Dentistry, Rochester, New York

PracticeUpdate ® is a registered trademark of Elsevier Inc. ©2019 Elsevier Inc. All rights reserved. ABOUT For a complete listing of disclosures for each board member and editorial contributor, please refer to their profile on PracticeUpdate.com PracticeUpdate ’s mission is to help medical professionals navigate the vast array of available literature and focus on the most critical information for their patients and practice. PracticeUpdate Conference Series is a collection of key research from leading international conferences, reviewed by the PracticeUpdate editorial and advisory board, made available in print format. These news highlights and more are also available online at PracticeUpdate.com PracticeUpdate and the PracticeUpdate Conference Series are commercially supported by advertising, sponsorship, and educational grants. Individual access to PracticeUpdate.com is free. Premium content is available to any user who registers with the site. While PracticeUpdate is a commercially-sponsored product, it maintains the highest level of academic rigour, objectivity, and fair balance associated with all Elsevier products. No editorial content is influenced in any way by commercial sponsors or content contributors. DISCLAIMER The PracticeUpdate Conference Series provides highlights of key international conferences for specialist medical professionals. The ideas and opinions expressed in this publication do not necessarily reflect those of the Publisher. Elsevier will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. Please consult the full current Product Information before prescribing any medication mentioned in this publication. Although all advertising material is expected to conform to ethical (medical) standards, inclusion in this publication does not constitute a guarantee or endorsement of the quality or value of such product or of the claims made of it by its manufacturer. The production and distribution of this publication is sponsored by Sun Pharma ANZ. It contains content published in accordance with the editorial policies of Elsevier’s PracticeUpdate.com. Content was produced by Elsevier with no involvement by Sun Pharma ANZ. All content printed in this publication can be found on PracticeUpdate.com SALES Matthew Buttsworth m.buttsworth@elsevier.com Virginia Van Homrigh v.vanhomrigh@elsevier.com PRODUCTION Content was originally published on PracticeUpdate.com Editorial Manager A nne Neilson anne.neilson@elsevier.com Editorial Project Manager Carolyn Ng Designer Jana Sokolovskaja ISSN 2208-150X (Print) • ISSN 2208-1518 (Online)

Associate Editors

Ashish C. Bhatia MD, FAAD Assistant Professor, Clinical Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Medical Director, Dermatologic Research, DuPage Medical Group, Naperville, Illinois; Co-Director, Dermatologic, Laser and Cosmetic Surgery, The Dermatology Institute – Naperville, DuPage Medical Group

Eliot Mostow MD, MPH Head, Dermatology Section, Northeast Ohio Medical University; Professor, Northeast Ohio Medical University, Dermatology Section, Rootstown, Ohio; Assistant Professor, Clinical Medicine, Department of Dermatology, Case Western Reserve College of Medicine, Cleveland, Ohio; Chief, Wound Care Research, Akron General Medical Center, Akron, Ohio

Advisory Board

Sarah L. Chamlin MD Professor of Pediatrics and Dermatology, Northwestern University Feinberg School of Medicine; Attending Physician, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois

Jane Grant-Kels MD Professor of Dermatology, Pathology and Pediatrics; Founding Department Chair Emeritus; Vice Chair of the Department of Dermatology; Founding Director Emeritus of the UCONN Dermatopathology Lab and Dermatology Residency program; Director of the Cutaneous Oncology and Melanoma Program; University of Connecticut Health Center and School of Medicine, Farmington, Connecticut Christen Mowad MD Director of Contact and Occupational Dermatitis Clinic; Clinical Director for Geisinger Dermatology, Geisinger Medical Center, Danville, Pennsylvania

Editorial Contributors

Caroline Crabtree MD Dermatology Resident, University of Mississippi Medical Center, Jackson, Mississippi

Margaret Hammond MD Resident, Case Western University, Cleveland, OH

InYoung Kim MD, PhD Resident, Dermatology, Case Western University Hospital, Cleveland, Ohio

Caitlyn Reed MD Dermatology Resident, University of Mississippi Medical Center, Jackson, Mississippi

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Expert Outlines Nonsurgical Options for Diffuse Epidermal Field Cancerization Surgical excision risks “fatiguing” patients and may place themat higher risk for metastasis.

P atients with diffuse field cancerization of the skin are often not good candidates for surgery. Nonsurgical options for this category of condi- tions were outlined in a presentation at WCD 2019. “We all see a lot of patients who have diffuse field cancerization, and I think of actinic keratosis and squamous cell in situ as essentially the same thing,” said Chrysalyne D. Schmults, MD, of Brigham and Women's Hospital and Harvard Medical School in Boston during her presentation, attended by Elsevier’s PracticeUpdate . “There is a histological spectrum. There is a clinical spectrum. You can’t really tell the difference too well between [the two] clinically. But, oftentimes, you can tell the difference between a dermally invasive squam and epidermally limited [actinic keratosis] squam in situ. … This is something that we as dermatologists can really get quite good at: discerning with our clinical eye what looks like epidermal disease and what looks like dermally invasive disease.” For patients with diffuse epidermal disease, she continued, “if you try to approach patients like this by excising every squamous cell in situ, these patients really get fatigued. They get discouraged with their care, and sometimes they even leave care for a period of time, which is bad because then they come back with more invasive disease. … We do need to treat this epidermal field canceriza- tion, however, because this epidermal disease is a set-up for dermally invasive squamous cell cancer. “These are the same types of patients who are going to end up with squam after squam after squam, and people who get 10 or more dermally invasive tumors ultimately start to accumulate a pretty high risk of local recurrence and nodal metastasis – in our data, about a 37% risk of local metastasis, and about one-quarter of these patients will finally get a tumor that metastasizes.” Inone recent trial, 932patientswhohadexperienced two or more basal cell or squamous cell cancers in the past were randomized to 5% 5-fluorouracil (5-FU) twice daily or placebo for 4 weeks. There was a 75% reduction over 12 months in the number of

squamous cell cancers that occurred in the active therapy group, compared with placebo. This effect was seen only in the first year, however. “This points to the chronicity of this condition and the fact that we need to keep treating and retreating these patients over and over again,” said Dr. Schmults. In another recent study, calcipotriol plus 5% 5-FU given for 4 days twice a day was compared with 5% 5-FU plus placebo. Even 3 years later, patients who received the combination therapy developed fewer new squamous cell cancers and had higher numbers of tissue-resident memory T cells in their skin than those who received 5-FU alone. “It seems that by adding the calcipotriol, you’re getting some kind of longstanding increased immune surveil- lance in the skin that helps people not to get so many dermal invasive squamous cell cancers,” Dr. Schmults suggested. With regard to the treatment of superficial basal cell carcinoma, a randomized study of 601 patients compared imiquimod cream for 6 weeks with 5% 5-FU twice daily for 4 weeks and methyl ami- nolevulinate photodynamic therapy (MAL-PDT) delivered twice, 1 week apart. Imiquimod was found to be superior to 5-FU and noninferior to MAL-PDT at 3 years. “So, if you have a biopsy and you know you have a superficial basal, then go ahead and use imiqui- mod on that lesion. But when you’re talking about field cancerization of a big field of disease, it’s impractical to use imiquimod, and 5-FU performs the best for squam in situ and [actinic keratosis] anyway,” concluded Dr. Schmults. Finally, a study out of Australia demonstrated that nicotinamide 500 mg taken twice daily in 386 patients who had had at least two nonmelanoma skin cancers in the previous 5 years reduced rates of squamous cell carcinoma by 30% and basal cell carcinoma by 20%, compared with placebo. Based on these findings, Dr. Schmults said, “we are putting pretty much all our patients [with] this kind of field cancerization epidermal disease on nicotinamide.”

Dr. Chrysalyne D. Schmults

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Role of Gut/ Cutaneous Dysbiosis in Dermatological Disease Highlighted More research is needed in this area.

I ntestinal and gut dysbiosis may play a far more substantial role in dermatologic conditions than previously recognized, according to a presenta- tion at WCD 2019. “In dermatology, there are two main fields of interest related to the study of the microbiota,” presenter Marco Pignatti, MD, from the University Clinic of Modena and Reggio Emilia in Italy, told Elsevier’s PracticeUpdate . “There are important functions of the gut microbiota in all chronic inflammatory diseases, like psoriasis, eczema, allergy, food allergy and autoimmune disease. And there is an important role for the skin microbiome in all pathologies in which a microbial agent is important in the pathogenesis, like acne, seborrheic dermatitis and rosacea. We have always considered them infectious diseases, but perhaps we should start to consider them as skin dysbiosis.” Currently, bacteria are considered to be the pri- mary pathogenic culprit in acne, fungi in seborrheic dermatitis, and protozoa in rosacea. All of the impli- cated microbes are also present in healthy skin, however. At present, these conditions are treated with antibiotic, antifungal and antiparasitic agents,

but “it might make more sense to create an equi- librium rather than kill one single component” of the cutaneous microbiome, suggested Dr. Pignatti. With regard to psoriasis, the gut microbiome is likely to play a more prominent role. He pointed out that there is a high degree of comorbidity between psoriasis and diseases of the gut, such as Crohn’s disease, and there is considerable overlap in the treatments for both. The gut microbiota comprises 10 times more cells than all our organs put together, he noted in his presentation. It weighs about 1.6 kg (about twice the weight of the heart and about 300 g more than the liver). It contains 3 to 8 million genes and has a level of metabolic activity equal to the liver. The key roles of the gut microbiota include maintain- ing the integrity of the intestinal wall, providing a defense against pathogens, eliminating toxins from the intestinal lumen, as well as modulating both immune and neuroendocrine function. Lack of diversity in the intestinal flora early in life has been linked with the development of allergies and asthma in childhood. “We know that the gut microbiota, skin microbi- ota, vaginal microbiota are all connected,” said Dr. Pignatti. “It is impossible to consider only one [in isolation]. We have to collect them together.” He pointed out how many skin diseases are exac- erbated by stress and explained that stress can influence gut health both directly and through life- style factors, including diet. This is a novel pathway through which dermatologists can consider the impact of stress on their patients’ skin. Some early clinical studies have linked gut health with skin disease and shown promising benefits of probiotics. In one study, 54% of acne patients showed evidence of alterations in intestinal flora.

Dr. Marco Pignatti

" We know that the gut microbiota, skin microbiota, vaginal microbiota are all connected. It is impossible to consider only one [in isolation]. We have to collect them together. "

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In-Vivo Confocal Microscopy Offers Diagnostic Benefits For SuspectedMelanoma When combined with dermoscopy, it helps reduce unnecessary excision of benign lesions. U se of in-vivo reflectance confocal microscopy (RCM) as a second non-invasive imaging technique following dermoscopy significantly reduced the number of unnecessary lesion excisions while still main- taining high sensitivity for diagnosis of melanoma, according to the results of a prospective trial.

“Previously, both retrospective and prospective observational studies assessed the diagnostic accuracy of in-vivo RCM combined with clinical and dermoscopic evaluation. [Thus,] a clinical trial on the additional utility of RCM was needed to further validate this tool,” Riccardo Pampena, MD, of the Centro Oncologico Ad Alta Tecnologica Diagnostica in Reggio Emilia, Italy and Giovanni Pellacani, MD, of the University of Modena and Reggio Emilia in Italy and WCD 2019 congress president indicated in a joint statement to Elsevier’s PracticeUpdate . The study investigators consecutively enrolled patients with at least one skin lesion suspected to be melanoma at three Italian centers (Modena, Reggio Emilia and Ravenna). A total of 1435 lesions were randomly assigned to one of two study arms: one consisting of dermoscopy plus RCM (n=746), and the other consisting of dermoscopy alone (n=689).

Dr. Riccardo Pampena

Small intestinal bacterial overgrowth (SIBO) has also been linked with rosacea in a 2008 study. Complete eradication of the SIBO with rifaximin therapy resulted in dramatic clinical improvement that was maintained for 9 months. Another study demonstrated the benefit of Lactobacillus paracasei (NCC 2461) on skin reac- tivity, and yet another showed benefits of this same probiotic for moderate-to-severe dandruff. In a 2003 study, the consumption of Lactobacillus rhamnosus strains by pregnant mothers and con- tinued by infants up to 6 months reduced the risk of eczema by almost 50% in at-risk children aged 2 and 4 years. A double-blind, randomized clinical trial showed that the administration of B. infantis led to the reduction of plasma levels of C-reactive protein and TNF-α that were elevated at baseline in patients with ulcerative colitis, chronic fatigue syndrome, and psoriasis. Studies with L. acidophi- lus and B. lactis have yielded similar results. Nevertheless, fully harnessing the therapeutic potential of the microbiome is hampered by lack of research, said Dr. Pignatti. Manufacturers of pro- biotics favor a direct-to-consumer approach that bypasses clinical trials. Some recent studies have failed to show a beneficial and lasting impact of pro- biotic supplementation on gut health. On reason for this, said Dr. Pignatti, is that supplementation with probiotics is not likely to be effective without diet and lifestyle habits that support a healthy microbi- ome. In particular, a diet high in whole foods, fiber and healthy fats and low in sugar and processed foods is essential. Other lifestyle factors such as good sleep habits and regular exercise can also play a positive role.

Dr. Giovanni Pellacani

As of an 8-month preliminary analysis, histopathological reports were available for a total of 717 lesions, 221 lesions in the dermoscopy plus RCM arm and 496 lesions in the dermoscopy alone arm. A total of 446 of the excised lesions (62.2%) were diagnosed as benign: 119 of the benign excised lesions were in the dermoscopy plus RCM arm, and 327 were in the dermoscopy alone arm. Meanwhile, 271 of the excised lesions (37.8%) were diagnosed as malignant. Of the malignant excised lesions, 102 were in the dermoscopy plus RCM arm and 169 were in the dermoscopy alone arm. Dr. Pampena and Dr. Pellacani reported that the addition of RCM meant that more than 60% of benign lesions could be saved from unnecessary excision, given the 99.1% sensitivity and 62.7% specificity seen with this device. “Our preliminary results support the indication for widespread use of confocal microscopy in melanoma diagnosis, combined with clinical and dermoscopic examination,” Dr. Pampena and Dr. Pellacani concluded. “New devices allowing a faster image acquisition are further supporting this process. “The most important practical implication is the possibility to save a [mean- ingful number] of benign lesions from unnecessary excision without losing melanoma cases,” Dr. Pampena and Dr. Pellacani noted. “We’ve calculated a number needed to excise of 1.4 with the additional use of in-vivo RCM, as compared to a value of 3.0 for clinical/dermoscopic examination alone. “The main unanswered question regards the economic impact of RCM on the healthcare system,” they added. “This aspect will be covered in the second part of the study, through a cost-benefit analysis.”

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Psoriatic Arthritis Expert Implores Dermatologists to Become More Involved in This Condition They are in the best position to facilitate early diagnosis, rapid access to effective therapy.

D ermatologists are ideally positioned to eval- uate high-risk patients for psoriatic arthritis and ensure that they obtain timely therapy, according to a presentation at WCD 2019. The presentation also highlighted the latest advances in the treatment of this condition. “Psoriatic arthritis is disabling, and delays in diagno- sis increase disability and pain,” emphasized Alice Gottlieb, MD, PhD, of New York Medical College during her presentation. The presence of psoriasis is an important risk factor for psoriatic arthritis, she explained. In fact, 84% of patients with psoriatic arthritis had psoriasis for an average of 10 to 12 years before they developed the condition. “In America, the [American Academy of Derma- tology] AAD guidelines for psoriasis care have come out to say that patients with psoriasis should be informed about the association [between pso- riasis and psoriatic arthritis] because they don’t [necessarily] know that their pain is associated with their psoriasis,” she continued. “Psoriatic arthritis should be considered in all patients with cutaneous psoriasis. I really feel strongly about this. It’s not just the moder- ate-to-severe [cases]. I’ve had patients come to joint replacement where the only psoriasis I could find was a little on the scalp. Patients who have signs and symptoms suspicious of psoriatic arthritis should be fully evaluated and treatment initiated, if not by the dermatologist, then the rheumatologist. So, it’s important to be sensitive to the diagnosis.” Early diagnosis is particularly important, given there are multiple effective therapies that not only control the signs and symptoms of the disease but have also been shown to inhibit radiographic progres- sion and improve quality of life. “The first people who can start treatment or get them to a rheuma- tologist is the dermatologist,” said Dr. Gottlieb. With the advent of effective biologic therapies for psoriatic arthritis, the role of methotrexate is

diminishing. For instance, the SEAM-PsA study randomized patients with active psoriatic arthritis to methotrexate monotherapy, etanercept mono- therapy, or a combination of both. Etanercept was more effective than methotrexate. “The addition of methotrexate to etanercept did not make a difference, so you can treat psoriatic arthritis with monotherapy,” concluded Dr. Gottlieb about this study. “The American College of Rheumatology [ACR] recommends a TNF-blocker over anything else as first-line for psoriatic arthritis, which is a big change,” she continued. “… If you’re looking at evidence-based medicine, TNF-blockers should be given ahead of methotrexate. However, I would still posit that they are behind the times. … I believe that both [the interleukin (IL)-17 inhibitors] ixekizumab and secukinumab should be first-line of psoriatic arthritis, in the absence of inflammatory bowel disease, because they inhibit radiographic progression in addition to controlling signs and symptoms. … They work as well in the joints, they work better in the skin than the TNF-blockers, and [they are] even safer.”

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" Psoriatic arthritis should be considered in all patients with cutaneous psoriasis. I really feel strongly about this. It’s not just the moderate- to-severe [cases]. I’ve had patients come to joint replacement where the only psoriasis I could find was a little on the scalp. "

Another IL-17 inhibitor, bimekizumab, has been shown in a phase II study to pro- duce an ACR20 at 24 weeks in 80% of patients. Dr. Gottlieb compared this with ACR20 rates of 60% with ixekizumab and 57.4% with adalimumab, both of which are currently FDA-approved in the United States for use in psoriatic arthritis. Even more impressive, bimekizumab produced an ACR50 in 70% of patients at week 12. The results of phase III trials are needed before approval of bimekizumab can be considered. “If they confirm the results, that would be moving the bar higher for clinical efficacy in psoriatic arthritis. So, this is one to watch,” said Dr. Gottlieb. A study presented in 2019 at the annual meeting of the European League Against Rheumatism (EULAR) compared ixekizumab and adalimumab head-to- head for psoriatic arthritis in a phase IV, open-label, assessor-blinded study in about 560 patients. The primary endpoint was the proportion of patients achieving both ACR50 and a Psoriasis

Area Severity Index (PASI) 100 at week 24. Ixekizumab was the better performer, with 36% of patients achieving this combined endpoint, compared with 28% of patients taking adalimumab. Ixekizumab was noninferior to adalimumab with respect to ACR50 but superior with respect to PASI 100 (60% vs 40%). Dr. Gottlieb highlighted that improve- ments in skin symptoms are important, as her own research demonstrates that quality of life scores are much higher in patients with psoriatic arthritis when both

their arthritis and their skin symptoms are well-controlled. An upcoming new class of drugs for the treatment of psoriatic arthritis is the IL-23 inhibitor class. In a phase II trial, gusel- kumab resulted in significant control of signs and symptoms of disease in 58% of patients. Results of phase III trials will be available soon. Risankizumab may have less potential, with a phase II study showing 62% achieving ACR20, but with no dose response and no significant improvement in quality of life.

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Two-Year Study Confirms Long-Term Benefits of Risankizumab in Psoriasis Over time, patients on risankizumabmaintained clear skin or had increased clearing. R isankizumab provides a durable response for psoriasis in a trial that followed patients on continuous therapy for up to 104 weeks, findings presented at WCD 2019 reveal. weeks of risankizumab re-treatment, 83.7% of these patients regained sPGA 0/1. Risankizumab was well-tolerated. Safety was generally compa- rable in the continuous-therapy and the placebo groups.

Risankizumab is a humanized IgG1 monoclonal antibody that selectively inhibits interleukin (IL)-23 through binding p19. It was recently FDA-approved in the United States for use in psoriasis. It is also approved by the European Medicines Agency for this indication. “Targeting p19 has shown higher levels of efficacy [in psoriasis], as high or higher than biologics that have already been on the market,” study coauthor Melinda Gooderham, MD, of Queen’s University School of Medicine in Kingston, Canada, told Elsevier’s PracticeUpdate . “The nice thing is that, with the higher levels of efficacy, you don’t compromise safety. You have a clean safety profile. There are no new concerns. If anything, there are fewer safety concerns than we see with the current biologics on the market.” IMMhance was a two-part, phase III, multinational, double-blind study in patients with moderate-to-severe plaque psoriasis. In the first part of the study, after 16 weeks of treatment, a greater pro- portion of the 407 patients treated with 150 mg of risankizumab met the coprimary endpoints of Psoriasis Area and Severity Index (PASI) 90 and static Physician’s Global Assessment (sPGA) 0/1, compared with the 100 patients on placebo (P < .001). In the second part of the trial, led by Andrew Blauvelt, MD, of the Oregon Medical Research Center in Portland, responders to initial risankizumab treatment (defined as an sPGA 0/1) at week 28 were stratified by weight and prior TNF inhibitor exposure and then re-randomized in a 1:2 fashion to continuous risanki- zumab every 12 weeks (n=111) or to placebo (n=225). After week 32, patients who relapsed, as defined by an sPGA ≥3, were re-treated with open-label risankizumab 150 mg. The primary and ranked secondary efficacy endpoints were the proportion of patients who maintained sPGA 0/1 at weeks 52 and 104, respectively, using non-responder imputation. Safety was also assessed in all patients. At week 52, 87.4% of patients re-randomized to continuous risankizumab maintained sPGA 0/1, and 81.1% maintained it at week 104. In contrast, sPGA 0/1 was maintained in 61.3% of pla- cebo at 52 weeks and 7.1% at 104 weeks (P < .001 for both time comparisons). By week 94, 73% of patients receiving continuous risankizumab had completely clear skin, defined as an sPGA 0. “That’s the highest level of sPGA 0 we have seen with any biologic,” said Dr. Gooderham. “Usually, we see a bit of a drop-off as you lose efficacy in some patients over time, but we did not see that with this medication. We saw the levels increasing, with more patients becoming clear the longer they were being treated. … [And] we know from many other studies that patients with [completely] clear skin have a better quality of life.” Overall, 153 of the 225 responders at week 28 who were re-randomized to placebo experienced relapse (68%). After 16

“This is a chronic condition, … a disease that people suffer with for decades,” said Dr. Gooderham. “If week 16 results look great, but in 2 years they are losing response, that is not helping us out in the long run. So, with therapy where we see patients staying clear and more patients becoming clear over time, we can be sure their chronic disease will be controlled chronically. … We shouldn’t have any tolerance for psoriasis hanging around now that we know we can clear it with such high levels.” " We shouldn’t have any tolerance for psoriasis hanging around now that we know we can clear it with such high levels. " www.practiceupdate.com/c/85591

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Oral Baricitinib Relieved Symptoms of Atopic Dermatitis In Two Phase III Trials If approved, this novel agent may help fill an unmet clinical need.

T he JAK inhibitor baricitinib significantly relieved symptoms of moderate-to-severe atopic der- matitis relative to placebo, according to the results of two identical, double-blind phase III trials BREEZE-AD1 and BREEZE-AD2. Baricitinib shows potential to fill an unmet need in atopic dermatitis, study presenter Eric Simpson, MD, of the Oregon Health and Science University in Portland told Elsevier’s PracticeUpdate . “There are no FDA-approved oral therapy options for moderate-to-severe atopic dermatitis, except for oral steroids, which are not appropriate for long- term treatment. A big therapeutic gap exists [for] a safe and effective long-term oral therapy,” he said. In the BREEZE-AD1 (n=624) and BREEZE-AD2 (n=615) trials, patients were randomized 2:1:1:1 to receive placebo or baricitinib at doses of 1 mg, 2 mg, or 4 mg, each for 16 weeks. The primary endpoint was proportion of patients achieving an Investigator’s Global Assessment (IGA) score of 0

or 1 with a ≥2-point improvement from baseline at week 16. Significantly more patients achieved the primary endpoint when receiving baricitinib 4 mg (16.8% in BREEZE-AD1 and 13.8% in BREEZE-AD2) or baricitinib 2 mg (11.4% in BREEZE-AD1 and 10.6% in BREEZE-AD2), rather than placebo (4.8% in BREEZE-AD1 and 4.5% in BREEZE-AD2). In addition, significantly more patients achieved a 75% reduction in Eczema Area and Severity Index (EASI75) when receiving baricitinib 4 mg (24.8% in BREEZE-AD1 and 21.1% in BREEZE-AD2) or baricitinib 2 mg (18.7% in BREEZE-AD1 and 17.9% in BREEZE-AD2), rather than placebo (8.8% in BREEZE-AD1 and 6.1% in BREEZE-AD2). “Clinically relevant reductions in itch were seen very soon after dose administration, with very clear and statistically significant changes detected at 1 week [for baricitinib 4 mg],” Dr. Simpson said. Statistically significant changes were detected as early as week 2 for baricitinib 2 mg. “The majority of patients experienced clinically rele- vant improvements in quality of life and symptoms within the first 1 to 2 weeks,” he added, including nighttime awakenings, skin pain, dermatology life quality index, and Patient-Oriented Eczema Measure (POEM), for both baricitinib 4 mg and baricitinib 2 mg. Adverse events occurred in 55% of patients receiv- ing placebo, in 54% of those receiving baricitinib 1 mg, in 58% receiving baricitinib 2 mg, and in 56% of patients receiving baricitinib 4 mg. The most common reported adverse events were headache and nasopharyngitis. Serious adverse events were reported among 3% of patients receiving placebo, 4% receiving baric- itinib 1 mg, 1.2% receiving baricitinib 2 mg, and 1.2% of patients receiving baricitinib 4 mg. “The study was very reassuring, as it found treatment with baricitinib at the doses used was extremely safe, with no increase in total adverse events above placebo,” Dr. Simpson concluded. He noted that future work will evaluate long-term safety and efficacy of baricitinib as well as its effects in the pediatric population. “This is the first step towards applying for baricitinib approval in Europe and Japan. Several more phase III studies are underway.” The BREEZE studies were supported by Eli Lilly and Company.

Dr. Eric Simpson

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WCD 2019 • PRACTICEUPDATE CONFERENCE SERIES

Perils of Private-Equity Dermatology Practices Many and Far-Reaching Potential to affect both practice and access to care.

A warning against private-equity dermatology practice was delivered in a presentation at WCD 2019: “Is private equity-controlled medi- cal care the kind of medical care that we want to be a part of?” presenter Jane M. Grant-Kels, MD, from UConn Health in Farmington, asked the audience. “The running of a dermatology practice in the United States, or anywhere, is running a small business,” said Dr. Grant-Kels. “Overhead is going up. There is a vocabulary list of new paperwork and bureaucracy. There are contracts that you need an attorney to understand that you have to sign with insurers, and it takes a very sophisticated physician to understand what they are signing. There are mandated electronic medical records, and a new phenomenon is that medical students are graduating with more debt than they've ever had.” In addition, older dermatologists eyeing retirement are looking to sell their practices. This opens the door for private equity, and the impending takeover is alarming. Currently, about 10% of dermatology practices in the United States are controlled by pri- vate equity. In 2009 there were 229 dermatology practices bought by private equity. In 2019, there were 747. “They are bragging that in 5 years they are going to own 80% of dermatology in the United States,” said Dr. Grant-Kels. The notion of partnering with a private equity firm can be appealing on the surface, but Dr. Grant- Kels describes it as “a pig with lipstick.” A private equity firmmight easily offer to pay a dermatologist the equivalent of six times the practice’s annual earnings before interest, taxes, depreciation and amortization. This can amount to a huge windfall and certainly more than dermatologists could hope to earn by selling their practices to anyone else. There are other benefits as well. Private equity firms, noted Dr. Grant-Kels, are “good at centraliz- ing practice and lowering overhead. They are good at running the business, streamlining them, making themmore profitable, and relieving dermatologists of management [responsibilities].” But the disadvantages far outweigh the benefits. “Private equity firms and venture capitalists are interested in one thing: making money,” she said.

Dr. Jane M. Grant-Kels

“Those of us in medicine have many other goals, and many of us make decisions for our patients where we actually lose money because patient care comes first. I don’t see how these values can overlap.” Dermatologists are usually required to stay on as employees but lose much of their autonomy, right down to being mandated what equipment and instruments to purchase and use. Typically, 20% of the profits of the practice go directly to the equity partners, which makes reinvesting in the business difficult. Private equity firms may let go of more seasoned physicians in the practice, replacing them with younger physicians, who will work for less, as well as physician extenders such as nurse practitioners and physicians’ assistants. A single physician may oversee as many as 5 to 10 physician extenders, who often see new patients or perform complex diagnoses and procedures that are beyond their scope of training. The pri- vate equity firmmay also mandate more expensive treatment options, even if it goes against the patient’s best interests. “Any primary skin cancer on the face has to be sent for Mohs, even if you think you can excise it,” said Dr. Grant-Kels.

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" Private equity firms and venture capitalists are interested in one thing: making money. Those of us in medicine have many other goals, and many of us make decisions for our patients where we actually lose money because patient care comes first. I don’t see how these values can overlap. "

“They offer a young dermatologist a pretty good salary to start, and then they ‘normalize’ those sal- aries and lower them,” she continued. “They make them sign a noncompete [agreement]. … You owe your soul to them because the noncompetes can be very wide and very unreasonable. And although you could fight them if you go to court, that's very expensive to do it. Most young people don't have the funding to do that.” There are wider consequences. Private equity firms are starting their own residencies and then hiring their own residents. “Residents are paid an unlivable wage and are [therefore] required to bor- row from the private equity practice. When they graduate, they immediately have to pay it back or work for the private equity firm,” said Dr. Grant-Kels. “It’s a form of indentured servitude.” Specialists are hired away from academic medical centers, mak- ing it more difficult to train new dermatologists in academic settings. Private equity firms purchase an “anchor” practice and then buy up other practices in the area, cre- ating “mega-groups.” With the focus set on profits, practices in disadvantaged communities or those that largely serve more complex cases or Medicaid patients will close. “Ultimately, there will be bank- ruptcies, lack of dermatology jobs, lack of access

to care for patients, and loss of diversity in practice,” predicted Dr. Grant-Kels. “I think private equity is not the model that we should aspire to,” she concluded. “You lose control. Patients are not notified that the practice has been sold to private equity. I do not believe that the phy- sician extender model, to the extent that they are using it, is a good one. I think the consequences of private equity dermatology are huge, particularly as it relates to education. It’s going to have a huge impact on residencies. It’s going to have an impact on access, … and I think it's going to impact the work/life satisfaction of dermatologists who are used to controlling their own environment.”

www.practiceupdate.com/c/85583

WCD 2019 • PRACTICEUPDATE CONFERENCE SERIES 11

Treatment History May Affect Effectiveness of Some Systemic Therapies for Psoriasis Findings could help clinicians choose optimal therapies for patients.

U sers of ciclosporin and acitretin who had used another systemic therapy for psoriasis in the past may be less likely to experience a reduction in psoriasis disease than those treated with these options as a first-line approach, accord- ing to results of a real-world, register-based study. “Patients with moderate-to-severe psoriasis are commonly prescribed non-biologic systemic therapies, including methotrexate, ciclosporin, acitretin, and fumaric acid esters,” study investi- gator Kayleigh J. Mason, PhD, of the University of Manchester in the United Kingdom, told Elsevier’s PracticeUpdate . “However, the effectiveness of these therapies in clinical practice is poorly under- stood, despite their widespread use.” For this real-world effectiveness study, investiga- tors used the British Association of Dermatologists Biologic and Immunomodulators Register (BADBIR),

a pharmacovigilance register investigating the long- term safety of systemic therapies in patients with psoriasis. The investigators identified 4113 patients with mod- erate-to-severe psoriasis in the register between 2007 and 2017 who received methotrexate, ciclo- sporin, acitretin, or fumaric acid esters with at least 6 months of follow-up. Among these patients, 1991 (48%) had been prescribed methotrexate, 1022 (25%) had been prescribed ciclosporin, 767 (19%)

Dr. Kayleigh J. Mason

Topical Ruxolitinib Shows Promise inRelieving Vitiligo Lesions A treatment for vitiligo approved by the United States Food and Drug Administration (FDA) remains an unmet clinical need. T opical ruxolitinib, a selective JAK1/ JAK2 inhibitor, significantly improved re-pigmentation of facial vitiligo active in vitiligo. The study was sponsored by Incyte, manufacturers of a proprietary topical formulation of ruxolitinib.

lesions in adult patients at 24 weeks com- pared with vehicle alone, according to the results of a dose-ranging phase II study. “There are about 3 million people who suf- fer with vitiligo in the United States, and yet [there is] no FDA-approved treatment for re-pigmentation,” David Rosmarin, MD, of the Tufts Medical Center in Boston, told Elsevier’s PracticeUpdate . “Patients with vitiligo often are stigmatized and have a compromised quality of life. … We are in need of new therapies for vitiligo.” Ruxolitinib is a nonsteroidal anti-inflam- matory therapy that functions by inhibiting the JAK pathway, which appears to be

The investigators found that significantly more patients achieved at least a 50% improvement from baseline in the Facial Vitiligo Area Severity Index (F-VASI50) at 24 weeks under all ruxolitinib-containing treatment regimens tested, relative to the vehicle control, meeting the study’s primary endpoint. “A treatment response was seen as early as week 8 in most treatment groups,” said Dr. Rosmarin. For the study, the investigators enrolled 157 adults aged 18 to 75 years with vitiligo who had depigmented areas of at least

PRACTICEUPDATE CONFERENCE SERIES • WCD 2019 12

used once-daily achieved a F-VASI75, compared with none on the vehicle group. Finally, 13% of patients using once-daily 1.5% ruxolitinib and 9% using the same dose twice-daily achieved F-PhGVA scores of ‘clear’ or ‘almost clear’, com- pared with none of the patients receiving vehicle control. The investigators found that ruxolitinib cream was generally safe and well- tolerated, using all of the dosing schemes included in the trial. “This is the largest vehicle-controlled, randomized, double-blind, well-designed study ever done in vitiligo,” said Dr. Rosmarin. “The results are very promising. I look forward to the phase III program, which will commence shortly. Hopefully, it will lead to the first medication FDA- approved for re-pigmenting vitiligo. “We still have more information to find out,” he stressed. “For example, what clinical characteristics or baseline demograph- ics make patients responders or not?” He also noted that it is still unknown if “patients continue treatment beyond week Upon multivariate analysis, prevalent users of acitretin were less likely to achieve a PASI <3 relative to incident users (adjusted odds ratio 0.67), as were prevalent users of ciclosporin (adjusted odds ratio 0.64). In the case of ciclosporin, the study authors suggested these find- ings may reflect its intermittent, short-term use in clinical practice. patients who had previously been pre- scribed another systemic therapy were classified as “previous systemic.” The proportions of incident, prevalent, and previous systemic users were similar for methotrexate, ciclosporin, and acitre- tin, but differed for fumaric acid esters. Whereas methotrexate, ciclosporin, and acitretin followed an approximate 2:1:2 ratio of incident to prevalent to previ- ous systemic use, patients prescribed fumaric acid esters were comparatively more likely to have received previous systemic therapy (66%) and less likely to be prescribed these agents as a first-line approach (19%). Overall, 34% of patients receiving ciclo- sporin achieved PASI <3, followed by methotrexate (30%), fumaric acid esters (25%), and acitretin (21%). Notably, the investigators used first PASI reported after initiating therapy for this analysis.

The BADBIR investigators did not iden- tify any significant differences in odds of achieving PASI <3 between prevalent or previous systemic user of methotrexate or fumaric acid esters and incident use. Dr. Mason suggested that the “guidelines on systemic therapies in the management of psoriasis could be revisited to include expected levels of effectiveness and rea- sonable time frames, to ensure patients are not left on suboptimal therapies. By considering these findings, we hope that our data will help in clinical decision-mak- ing and aid in identifying themost effective first-time systemic therapy for patients with moderate-to-severe psoriasis.” She noted that future work will focus on identifying patterns of response among psoriasis patients prescribed various systemic therapies. “We are now working to establish whether there are patterns of treatment response, non-response, and/or partial response across these therapies and whether the time spent on these therapies differs by treatment response groups,” Dr. Mason said. “For example, how long are non-re- sponders on therapy before stopping or switching? What are the most common reasons for stopping/switching systemic therapies?”

0.5% of the surface area of the face and at least 3% body surface area depigmen- tation in non-facial areas. Patients were randomized across five treatment arms consisting of 24 weeks of daily ruxolitinib at 1.5%, 0.5%, and 0.15% strength, twice daily ruxolitinib at 1.5% strength, and vehi- cle control. The primary endpoint was percentage of patients achieving F-VASI50 at week 24, with secondary endpoints including proportion of patients achieving a Facial Physician Global Vitiligo Assessment (F-PhGVA) score of 0 ‘clear’ or 1 ‘almost clear’ at week 24, as well as safety and tolerability. Patients will continue to be followed-up for a full 104 weeks. The best results were obtained using once-daily 1.5% ruxolitinib cream (50% achieving F-VASI50) and twice-daily 1.5% ruxolitinib cream (45% achieving F-VASI50), compared with vehicle control (3% achieving F-VASI50, P < .001). In addi- tion, 30% of patients on the highest dose of topical ruxolitinib cream 1.5% twice a day and 17% of those on the same dose Patients included in the BADBIR study were classified according to their treat- ment history: Those who had received their first systemic therapy were classified as “incident,” whereas patients prescribed registration systemic therapy previously were classified as “prevalent,” and had been prescribed acitretin, and 335 (8%) had been prescribed a fumaric acid ester.

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24, will they continue to re-pigment?” Finally, questions remain as to whether the medication can produce a remission or whether depigmentation will recur when treatment is stopped.

www.practiceupdate.com/c/85596

© WCD 2019

WCD 2019 • PRACTICEUPDATE CONFERENCE SERIES 13

Experimental Topical Tropomyosin Receptor Kinase A Inhibitor Improved Psoriasis Severity Phase III trials are in the works, pending regulatory approval.

S NA-120 (pegcantratinib), a topical, non- steroidal inhibitor of tropomyosin receptor kinase A (TrkA) significantly improved measures of psoriasis disease severity, although patient-reported itch severity was not significantly improved, according to the results of a phase IIb study. “It was important to conduct the study to reaffirm data from earlier … work regarding the impor- tant role than the [nerve growth factor] NGF/ TrkA pathway plays in psoriasis pathogenesis,” presenter Paul F. Lizzul, MD, PhD, of Sienna Biopharmaceuticals, manufacturer or SNA-120, told Elsevier’s PracticeUpdate . “… NGF and TrkA are overexpressed in psoriasis patients. In those psoriasis patients who are more itchy, … TrkA is even further upregulated.” Thus, scientists “could think of itch as a clinical biomarker of elevated NGF and/or TrkA.” Lizzul highlighted the fact that SNA-120 “works at the intersection between the skin, the nervous, and the immune systems. And it does so with a very good safety profile, with no to very low systemic exposure.” For this double-blind study, investigators enrolled 208 adult aged ≥18 years with mild-to-moderate psoriasis and at least moderate itch, defined as ≥5 on the Itch Numeric Rating Scale (I-NRS). Patients were randomized to receive one of three condi- tions: twice daily SNA-120 at 0.05% concentration, twice daily SNA-120 at 0.5% concentration, or vehicle control, each for 12 weeks.

The prespecified primary endpoint for the study was change in itch, as measured by the I-NRS score from baseline to week 8. Prespecified secondary endpoints included the composite of a ≥2-point decrease in Investigator Grade Assessment (IGA) and ‘clear’ or ‘almost clear’ as well as a 75% reduc- tion in Psoriasis Area and Severity Index (PASI 75) at week 12. The study failed to meet the primary endpoint, in that mean reduction in I-NRS score was not signif- icantly better at week 8 among patients receiving 0.05% SNA-120 (4.2) or 0.5% SNA-120 (3.6) than among patients receiving vehicle control (3.9). “While itch did not statistically separate from vehicle in this study,” Dr. Lizzul noted, “this was likely attrib- uted to a high vehicle response on the subjective measure of itch, related to expectations and bias [deriving from] heavy emphasis and interrogation on this symptom.” He predicted that less “intensive and focused interrogation on this subjective symp- tom in future studies should recapture the clear separation observed in earlier studies, which did not overemphasize the benefit to patients”. SNA-120 did produce clinically meaningful, statisti- cally significant improvements in psoriasis severity at week 12, however. Relative to vehicle control, subjects who received 0.05% SNA-120 were sig- nificantly more likely to achieve the composite of ≥2-point improvement on IGA and ‘clear’ or ‘almost clear’ (29% vs 13%; P = .036) or PASI75 (27% vs 13%; P = .045) at week 12. However, 0.5% SNA- 120 did not repeat the same statistically significant response in IGA and PASI75 scores.

" …the results of this trial confirm what astute clinicians have noted for many years, that peripheral nerves play an important role in psoriasis. The data highlight the link between these clinical observations and the basic mechanisms and pathology underlying them. " PRACTICEUPDATE CONFERENCE SERIES • WCD 2019 14