By Victoria Houghton, managing editor
Ten years ago, Emma Guttman-Yassky, MD, PhD, was knocking on doors in an attempt to garner interest from pharmaceutical companies in atopic dermatitis research. “I really tried to convince these companies to go for atopic dermatitis, but no company wanted to hear about it,” said Dr. Guttman, professor and vice chair, department of dermatology, and the director of the Center for Excellence in Eczema and the Laboratory for Inflammatory Skin Diseases at the Icahn School of Medicine at Mount Sinai in New York. Although roughly 15 to 20% of children and 4 to 7% of adults suffer from atopic dermatitis worldwide, at the time all eyes were on the psoriasis space, said Dr. Guttman.
Today, things are different. “Now many of these companies gradually became interested in atopic dermatitis.” Dr. Guttman likens the atopic dermatitis story to several aspects of the psoriasis narrative. “Similar to psoriasis, atopic dermatitis is an immune-driven disease and can be targeted using immune-based targeted therapies.” However, “atopic dermatitis is a more heterogeneous disease with different phenotypes and we are starting to learn that there may be no one-size-fits-all approach to treating the condition.”
Dermatology World talks with experts about where things stand with medicine’s understanding of the pathogenesis of atopic dermatitis and how this understanding is shaping the development of potential treatment options for this heterogeneous condition.
Therapeutic wins
Merely two years ago, the treatment options for atopic dermatitis patients were fairly limited. “The only U.S. FDA-approved systemic therapy was prednisone,” said Robert Sidbury, MD, MPH, co-chair of the National Eczema Association Scientific Advisory Committee and division chief of dermatology at Seattle Children’s Hospital. “If you ask a room of dermatologists what their least-favorite drug for atopic dermatitis is, it would be the prednisone.”
Enter: crisaborole (Eucrisa) and dupilumab (Dupixent). The FDA approved crisaborole — a topical PDE-4 inhibitor — and dupilumab — an IL-13 and IL-4 inhibitor — in December 2016 and March 2017, respectively. Now that physicians and their patients have had time to test these newly approved drugs in real life, how are they faring?
Crisaborole
“With crisaborole, the efficacy is modest,” said Eric Simpson MD, MCR, professor of dermatology at Oregon Health and Science University School of Medicine. “However, it does provide a nice option for a non-steroidal approach.” Lisa Beck, MD, Deans professor of dermatology and medicine at the University of Rochester Medical Center, agrees and adds, “There is the occasional person with very good response to crisaborole, but I think this is unfortunately a pretty rare event. I must say I’ve been disappointed in its clinical efficacy.”
Additionally, Dr. Beck notes that a number of patients have reported burning and itching. “I was not originally counseling patients about this side effect because the phase 3 trials reported this side effect in only 4.4% of patients.” Despite Dr. Beck’s counsel, she still finds that many patients do not want a refill because they’re not willing to tolerate the side effects for what they perceive as a pretty minimal benefit, this is particularly true for pediatric patients — as the topical is approved for children as young as two.
Dr. Sidbury also finds that the cost of the medication can be a deterrent. “The original price I heard quoted was $600 for a 60 gram tube and that’s not accessible for anyone really for chronic use. However, the manufacturer has been very good at trying to use coupons and various strategies to make that more accessible,” said Dr. Sidbury.
Dupilumab
Conversely, for many patients with moderate-to-severe atopic dermatitis, dupilumab has been a game changer. “About 80 to 90% of our patients are finding that this drug is very beneficial to them,” said Dr. Beck. “It’s not at all uncommon that we hear from a subset of these patients that it’s life-altering therapy.” According to Dr. Beck, for many of these patients the itch relief is significant and is often noted within a week or two of starting treatment. “The relief is very clearly noteworthy and leads to significant elevation in patients’ mood. The improvement in the appearance of skin lesions tends to lag behind the itch reduction, but patients are very patient as their biggest complaint is the itch.”
Not everyone has a dramatic response to dupilumab, however, says Dr. Beck. Additionally, a number of patients report eye-related side effects. “We’ve seen a whole range of eye complaints: dry eyes, itchy eyes, and sometimes swelling of the eyelids.” However, Dr. Beck finds that the side effects are minimized when she counsels patients about proper eye care prior to initiating treatment.
In addition to ocular side effects, Dr. Beck notes that getting access to dupilumab has been challenging at times. “Dupilumab has been somewhat difficult to get prior authorization approval. However, like all new expensive biologics, it gets easier with time as insurances clarify their criteria for drug approval.”
Logical biologics?
With the success of dupilumab, is there really a need to develop new treatments in this space? For Brian Kim, MD, MTR, co-director of the Center for the Study of Itch and assistant professor of dermatology at Washington University School of Medicine in St. Louis, the answer is a definitive ‘yes.’ “This is a very sophisticated immune pathway. You have these cytokines that block inflammation and these cytokines that block itch. They’re all in the same family and I think a lot of those cytokines are very promising. Dupilumab is not the end of it. In my mind, I think it’s actually the beginning of it.”
Lebrikizumab and tralokinumab – IL-13
Despite the widespread success of dupilumab, much research is being devoted to understanding the significance of dupilumab’s IL-4 inhibition. Researchers have been inadvertently singling it out by studying IL-13 inhibitors lebrikizumab and tralokinumab. Additionally, “It’s always nice to have options because of the heterogeneity of the disease and because there will be patients who don’t respond to dupilumab or get adequate response,” said Dr. Simpson. “IL-13 blockers tralokinumab and lebrikizumab: Those are pretty safe bets that they should have some activity.”
So far, a phase 2 study of lebrikizumab indicated that 125 mg taken every four weeks with topical corticosteroids resulted in a significant reduction in Eczema Area and Severity Index (EASI) scores and was well tolerated in adults with moderate-to-severe atopic dermatitis (J Am Acad Dermatol. 2018 May;78(5):863-871.e11). Similarly, a phase 2b dose-ranging efficacy and safety study of tralokinumab in adults with moderate-to-severe atopic dermatitis found that 300 mg every two weeks over 12 weeks significantly improved the Scoring of Atopic Dermatitis (SCORAD), Dermatology Life Quality Index, pruritus numeric rating scale, and EASI 50 scores, with an acceptable safety profile (J Am Acad Dermatol. 2017 June; 76(6), Suppl 1: AB20). While these biologics look promising, Dr. Simpson remains cautiously optimistic. “Whether they will provide benefit or work in patients who fail dupilumab, we’ll just have to look at the phase 3 data.”
Nemolizumab – IL-31
For atopic dermatitis patients with a more intense component of itch, nemolizumab could be an option, said Dr. Beck. “Anti-IL-31 targets the cytokine that we think is a potential pruritogen. It’s an itch-inducing mediator.” Results of a study published in the New England Journal of Medicine showed lightning-fast improvements in itch with a 60% reduction in pruritus visual-analogue scale scores as early as four weeks into the trial (2017; 376:826-835). A subsequent 52-week study showed additional gradual improvement in the pruritus visual-analogue score (https://doi.org/10.1016/j.jaci.2018.03.018).
When it comes to EASI scores, however, nemolizumab doesn’t compare to dupilumab, says Dr. Beck. “What was a big concern was that the improvement in EASI appeared to be more modest than what we’ve been seeing with dupilumab.”
GBR 830 – OX40
Although its name doesn’t end in ‘mab,’ GBR 830 — an OX40 inhibitor — is another biologic that is piquing some interest as a potential treatment for atopic dermatitis. OX40 is a co-stimulatory immune receptor on the T cells. When overactive it contributes to an increased severity of autoimmune disease and promotes inflammation.
“OX40 antagonism is another treatment approach that is being studied and it seems to be successful in preliminary studies,” said Dr. Guttman. The results of a 12-week, phase 2a double-blind, placebo-controlled study were presented at the 2018 AAD Annual Meeting, indicating that 17 out of 23 patients who received intravenous infusions of GBR 830 on days one and 29 saw clinical improvements in EASI scores. The most common side effect was headache. In April, Glenmark Pharmaceuticals announced plans for a phase 2b trial of GBR 830.
Fezakinumab - IL-22
For atopic dermatitis patients with epidermal hyperplasia, IL-22 blockade looks increasingly promising, says Dr. Guttman, as IL-22 promotes epidermal hyperplasia and inhibits skin barrier function. Dr. Guttman, et al performed a randomized, double-blind, placebo-controlled trial with intravenous fezakinumab monotherapy every two weeks for 10 weeks, with follow-up until 20 weeks. The decline in SCORAD scores from baseline at 12 weeks was significantly stronger in the patients treated with fezakinumab and the most common reported side effect was upper respiratory tract infections (J Am Acad Dermatol. 2018 May; 78(5): 872-81.e6).
Although the paper acknowledges limitations such as a narrow sample size and no EASI or pruritus numerical rate scale assessments, Dr. Guttman is intrigued. “IL-22 shows promise in a subset of patients and will be interesting to follow.”
Yet for Dr. Beck, with all of these biologics, the question remains: How can you improve upon dupilumab? “I think it will be interesting to see how these drugs develop. However, I think that the question for any new drug is: How do you distinguish yourself from dupilumab? How do you look safer or more effective?”
JAKpot?
For some patients, the answer to the question about how to improve upon dupilumab is simple: Stop the injections. “The potential benefit of JAK inhibition is that patients can have an oral therapy,” said Dr. Simpson. Additionally, “It’s a slightly broader blockade of inflammatory mediators, so it can maybe handle the heterogeneity of the disease.” Additionally, Dr. Guttman adds, “You can stop and restart whenever you want. We need to remember that that’s something we cannot do with biologics.”
The excitement around JAK inhibitors has permeated throughout the house of medicine as well. “You have people who are very interested in these pathways for a lot of other indications and a lot of other disease states. There’s a new potential indication for JAK inhibitors in many realms — alopecia areata, vitiligo, and also in rheumatology,” said Dr. Kim. “I think excitement begets excitement.”
Baricitinib – JAK1/2
Baricitinib, an oral selective JAK1 and JAK2 inhibitor, modulates pro-inflammatory cytokine signaling, and has achieved some promising results in atopic dermatitis trials. In a recent phase 2, randomized, double-blind, placebo-controlled study, patients on 2 or 4 mg of baricitinib for 16 weeks saw improvements in EASI 50 scores, as well improved pruritus and sleep loss (J Am Acad Dermatol. 2018 Feb 1. pii: S0190-9622(18)30129-4).
However, the researchers acknowledged that patients were given a topical corticosteroid for four weeks prior to the study, and therefore longer studies evaluating baricitinib as a monotherapy are warranted. Currently, a phase 3 study is underway and is expected to be completed by the end of 2018.
Upadacitinib (ABT-494) - JAK1 inhibitor:
Similarly, JAK1 inhibitor upadacitinib also appears to be meeting its primary endpoints. At the 2018 AAD Annual Meeting, researchers presented results from a Phase 2b study evaluating upadacitinib in various once-daily doses for 16 weeks. The average percentage improvement from baseline in EASI scores ranged from 39, 62, and 74% for 7.5, 15, and 30 mg respectively by week 16. Additionally, the average percent change from baseline in the Pruritus Numerical Rating Scale was 40, 48, and 69% for 7.5, 15, and 30 mg respectively by week 16. The most common side effects were upper respiratory tract infections, acne, and atopic dermatitis worsening.
JAK/SYX – ASN002
Dr. Guttman is also intrigued by a dark horse that has recently entered the realm of potential JAK inhibitors for atopic dermatitis: ASN002. “This is a JAK/SYK inhibitor that shows promise.” The theory behind this oral JAK/SYK inhibitor is that it reduces the cytokine production and signaling involved in the Th2 and Th22 cytokine pathways.
At the 2018 AAD Annual Meeting, researchers presented results from a recent clinical proof of concept study indicating that ASN002 met its efficacy and safety endpoints. After four weeks of treatment, nearly all patients on either 40 or 80 mg once-daily doses achieved a 50% improvement in EASI 50 scores by week four. Additionally, patients reported a marked reduction in itch per the Numeric Rating Scale after four weeks. “Larger and longer studies are needed to show long-term disease control and safety over time,” said Dr. Guttman in a press release, “but this is very exciting news so far.” A phase 2b study is currently underway and is expected to be completed in July 2019.
Despite these intriguing study results with acceptable safety profiles, Dr. Beck remains cautious about the potential side effects of long-term use. “The oral JAK inhibitors appear to have pretty remarkable clinical improvement. The next step is to find the right dose that offers the best benefit but minimizes the side effects. Patients don’t like having to undergo regular drug monitoring for side effects and this is a drug category where I suspect it will be very unlikely that they will get approved without some requirements for routine blood monitoring.”
Overall, while these drugs are still in the development stages, Dr. Kim is delighted by the progress that has been made with atopic dermatitis treatments. “I think that in the future we’re going to see more personalized treatments in atopic dermatitis, where we can say, ‘You’re going to do well on dupilumab’ or ‘you have more itch-predominant atopic dermatitis so you’re going to do better on nemolizumab.’” Dr. Kim is also optimistic about the domino effect this research will have on other aspects of dermatology. “By studying this disease, we’ve actually been able to learn more about other chronic itch disorders. There’s much more to come beyond atopic dermatitis as a result of this investment in research. This is just a starting point for us.”
Check out the New and Emerging Therapies for Atopic Dermatitis Roundtable video from JAAD at http://olc.aad.org/diweb/catalog/launch/package/3/eid/2209349.