The 2017 AAD annual meeting, held March 3-7, in Orlando, Florida, was a grand affair, with attendance exceeding 18,000 dermatologists, medical fellows, medical students, and industry professionals. DRG’s dermatology expert Sangha Mitra was at the meeting, focusing on new developments in atopic dermatitis, psoriasis and expanded use of targeted therapies in dermatology.
Spotlight on atopic dermatitis (AD): For many years, the treatment landscape of AD has remained stagnant, with topical agents as the mainstay of treatment, and off-label use of systemic immunosuppressants, such as azathioprine and cyclosporine, largely seen in patients whose disease is inadequately controlled by topicals. The unmet need for better treatment options for patients with severe and/or refractory AD and the success of targeted therapies in other autoimmune indications, including another dermatology indication psoriasis, have driven research and development for new AD therapies. With the recent approval of a novel non-steroidal topical, Pfizer’s Eucrisa (crisaborole), and expected approval of the first AD biologic, Sanofi/Regeneron’s Dupixent (dupilumab) at the time of the conference, thought leaders believe that targeted AD treatment options will expand in the next ten years just like what happened for psoriasis in the past decade.
Owing to Eucrisa’s clean safety profile, there was a buzz around the drug. Experts believe that it will provide a much-needed alternative to topical corticosteroids (TCSs) and topical calcineurin inhibitors, both of which are plagued with safety concerns. However, dermatologists are concerned about the cost of Eucrisa and whether their patients will have access to the treatment through their health insurances. There was excitement and anticipation around the imminent approval of Dupixent, which has since received FDA approval on March 28, 2017. Dupixent is a targeted biologic that blocks both IL-4 and IL-13, important cytokines in the pathophysiology of AD. One-year Phase 3 CHRONOS1 study data showed that patients receiving a combination of Dupixent and topical TCSs achieved significantly improved disease severity outcomes compared to TCS monotherapy in adults with uncontrolled moderate-to-severe AD. The newly reported results built upon data presented last June for treatment after 16 weeks and showed that these improvements are sustained after 52 weeks of treatment. Phase II study results of another biological therapy, Chugai’s nemolizumab2 was highlighted at the conference; it targets IL-31, which is believed to be a key driver of pruritus, which is a persistent, annoying symptom in AD that disturbs sleep and quality of life of patients. In fact the primary endpoint of the Phase II trial was itch reduction, which nemolizumab was able to achieve. An interesting new treatment concept for AD, cutaneous microbiome “transplant” was discussed as a potential therapy. Frequently, AD patients have staphylococcus infection on their skin lesions. Specific strains of coagulase-negative staphylococci (CoNS) produce anti-microbial peptides, however AD patients are deficient in these beneficial strains. Preliminary studies have shown that reintroduction of antimicrobial CoNS strains on the infected skin reduced staphylococcus aureus colonization. Clinical trials3 are now underway to study the viability of this treatment in AD.
Advances in psoriasis treatment: Over the past decade, biologics have altered the landscape in the management of moderate to severe psoriasis by achieving improved skin clearance, control of symptoms and quality of life for hundreds of thousands of individuals affected. Unsurprisingly, advances and barriers in using biological therapies in psoriasis were discussed at length at the conference. Currently, there are seven FDA-approved biologics in the United States belonging to three separate drug classes: TNF-alpha inhibitors Humira (adalimumab, AbbVie), Enbrel (etanercept, Amgen), and infliximab (Janssen’s Remicade and Pfizer’s biosimilar Inflectra), the IL-12/23 inhibitor Stelara (ustekinumab, Janssen), and the IL-17 inhibitors Cosentyx (secukinumab, Novartis), Taltz (ixekizumab, Eli Lilly), and Siliq (brodalumab, Valeant). However, only a small proportion of patients benefit from these treatments because they are expensive therefore their use is often restricted by a patient’s disease severity and response to other less expensive treatments. Biosimilars are developed to provide comparable treatment to reference product at a lower cost. There were sessions dedicated on educating dermatologists on biosimilars. Dermatologists hope that biosimilars of TNF-alpha inhibitors will live up to the promise of decreasing cost and will increase access to biologic therapies.
Among new clinical data presented at the conference, focus was on extension studies, specific subtypes of psoriasis (nail, scalp, palmoplantar psoriasis) and detailed phase 3 trial data for some of the newer biologics. For Cosentyx, data from the extension study of SCULPTURE4 trial showed that efficacy was sustained for four years for patients on Cosentyx. Another study5 evaluating treatment withdrawal and retreatment in the extension studies from two other phase 3 trials showed that Cosentyx retreatment rapidly restored efficacy in patients relapsing after being withdrawn from therapy. Since psoriasis trials are generally short, 12 or 16 weeks, an occasionally heard criticism of head to head trials with Stelara, whose maintenance dosing is every 12 weeks, is the short duration of trials that likely does not allow full response to Stelara. Physicians perceive Stelara is underdosed and needs two maintenance dosing to achieve its optimal efficacy. Eli Lilly conducted a 24 week head to head trial (IXORA-S)6 and demonstrated that Taltz still showed superiority over Stelara. Findings from two pivotal phase 3 studies (VOYAGE 27 and NAVIGATE8) demonstrated Janssen’s IL-23 inhibitor guselkumab was superior to both Humira and Stelara. Additionally, in the NAVIGATE trial, patients with inadequate response to Stelara were either switched to guselkumab or stayed on Stelara and the results showed that treatment with guselkumab provided significant benefit to patients who were not achieving good skin clearance with Stelara, indicating patients with inadequate response to Stelara can move on to guselkumab treatment.
Among emerging therapies, Merck KGaA’s M10959, a novel bispecific nanobody (antibody with only heavy-chains) that targets both IL-17A and IL-17F, is being developed for psoriasis. Findings from a placebo controlled Phase I study evaluating efficacy and safety of M1095 in patients with moderate to severe psoriasis presented at the conference look encouraging and it will be interesting to see how the drug behaves in larger trials. A novel topical cream, tapinarof (GlaxoSmithKline’s GSK2894512) showed promising efficacy and safety in a Phase II trial10. For more than 25 years, no new topical therapy has been successfully developed for psoriasis. Drug developers are either developing new formulations of existing topicals or combining existing monotherapies, vitamin D analogs and topical corticosteroids, for fixed dose combinations.
Unmet need for targeted therapies in other dermatology indications: Pfizer’s Jak inhibitor Xeljanz (tofacitinib) failed to secure regulatory approval for psoriasis but the class may have use in other dermatology conditions such as alopecia areata, which causes hair loss and vitiligo, which causes skin discoloration. These diseases are very visible, patients suffer from both clinical symptoms and emotional stress, and they lack effective therapies. In the United States, Xeljanz is approved for rheumatoid arthritis. Case studies showed that off-label use of Xeljanz in alopecia areata patients resulted in regrowth of hair. Similar symptom improvements were also observed in patients with AD and vertiligo. While these results are encouraging, for regulatory approval in these conditions, clinical trials are needed, which are already in progress for AD11 and alopecia areata12.
Final thoughts: The pool of targeted therapies in dermatology grew larger this year with the addition of Siliq for psoriasis and Dupixent for AD. In the past three years, the dermatology space has seen the addition of 6 biologics, 1 novel oral therapy, and 1 novel topical treatment. Although, most of the development is happening in psoriasis, we have seen the introduction of biologics in hidradenitis suppurativa (Humira) and chronic idiopathic urticaria (Roche/Novartis’s Xolair), and we are now seeing expansion of targeted therapies in AD. The psoriasis pipeline shows no sign of slowing down, after approval of three IL-17s, a series of late-stage biologics of the novel anti-IL-23 class await entry to this ever-growing market. Also with the success of Celgene’s Otezla, the first targeted oral therapy in psoriasis and its growing use in the mild to moderate patient population, interest is high in developing oral therapies for other dermatology conditions such as AD and alopecia areata. Topical treatments are also being reinvented by targeted therapies.
The AAD meeting had a strong focus on “what’s next” with sessions devoted to late-breaking clinical research, emerging therapies, and also debate on whether newer biologics will become early-line therapies in psoriasis. Thought leaders highlighted undertreatment of psoriasis and AD and discussed how new targeted therapies as well as biosimilars can increase access to effective treatments. Also sessions devoted to comorbidities highlighted that AD and psoriasis are not just skin barrier diseases; in fact they are systemic diseases that need holistic care. Industry sessions were educative and focused on increasing awareness about new drugs such as Eucrisa, Cosentyx and how collaborative efforts of dermatologists and rheumatologists can improve care of patients with both psoriasis and psoriatic arthritis. The evening industry receptions provided a relaxing atmosphere to mingle with thought leaders and industry experts, fostered discussions around serious topics such as lack of a consensus assessment tool for AD, and offered a unique patient and healthcare provider perspective on Cosentyx use through the psoriasis treatment journey of the rock star Cyndi Lauper. Overall a highly stimulating and engaging conference and the count down now begins for the next meeting in 2018.
 Sanofi and Regeneron Announce Presentation of Positive Data from Long-Term Pivotal Phase 3 CHRONOS Study of Dupixent (dupilumab) in Moderate-to-Severe Atopic Dermatitis. Sanofi and Regeneron Pharmaceuticals, press release, March 4, 2017.
 Ruzicka T., et. al. Anti–interleukin-31 receptor A antibody for atopic dermatitis. N. Engl. J. Med, 2017; 376: 826-835.
 Validation of the short-term antimicrobial action of transplanted bacteria, NCT01959113, accessed March 27, 2017.
 Secukinumab provides sustained improvements in dermatology-specific quality of life in moderate to severe psoriasis patients through 3 years of treatment: results from the SCULPTURE extension study. American Academy of Dermatology Annual Meeting; 2017, Orlando, abstract# 4223.
 Secukinumab retreatment shows rapid recapture of treatment response: an analysis of a phase 3 extension trial in psoriasis. American Academy of Dermatology Annual Meeting; 2017, Orlando, abstract# 4879.
 New head-to-head data shows significantly higher response rates for Lilly's Taltz (ixekizumab) compared to Stelara (ustekinumab) in patients with moderate-to-severe plaque psoriasis. Eli Lilli, press release, March 4, 2017.
 Efficacy and safety of guselkumab compared with adalimumab for the treatment of moderate to severe psoriasis: results from the phase 3, double-blind, placebo- and active comparator-controlled VOYAGE 2 trial. American Academy of Dermatology Annual Meeting; 2017, Orlando, abstract# 4749.
 Efficacy of switching from ustekinumab to guselkumab in patients with moderate-to-severe plaque psoriasis: results from the NAVIGATE study. American Academy of Dermatology Annual Meeting; 2017, Orlando, abstract# 4915.
 Safety and efficacy of multiple ascending doses of subcutaneous M1095, an anti-interleukin-17A/F bispecific nanobody, in patients with moderate-to-severe psoriasis. American Academy of Dermatology Annual Meeting; 2017, Orlando, abstract# 5511.
 Dose-finding study of GSK2894512 cream for treatment of plaque psoriasis, Late-breaking research forum clinical trials. American Academy of Dermatology Annual Meeting; 2017, Orlando, F056.
 Study to evaluate Pf-04965842 in subjects with moderate to severe atopic dermatitis, NCT02780167, accessed March 27, 2017.
 Study to evaluate the efficacy of tofacitinib in moderate to severe alopecia areata, totalis and universalis, NCT02299297, accessed March 27, 2017.