After the past year, we could all use a little comfort and relaxation this holiday season. A recent segment on NBC’s “Today” show predicted that the trend this year is “buying less but better,” and…
Published On: Apr 5, 2021
Last Updated On: Jun 3, 2021
The pipeline of promising treatments for atopic dermatitis (AD) is undergoing unprecedented expansion, and includes topical, oral and injectable therapies. In January 2021, the first article in this series reviewed what is coming for a new class of oral and topical drugs, the Janus kinase inhibitors (JAKs). In this second article, we take a look at new biologics on the horizon. Interest and growth in this area of drug development has been fueled by research highlighting the contributions of the immune system in disease onset and progression, as well as results from clinical trial and real-world use of dupilumab (i.e. Dupixent), the first biologic FDA-approved for moderate-severe AD.
Immunology of eczema
AD is caused by both an “elevated” immune response within the skin and a defective skin barrier which can have underlying genetic or environmental factors (like allergens). The bacteria that call the skin home (such as Staphylococcus aureus) can also play a role in AD.1
Years of dedicated scientific studies have teased out important clues about specific immune responses that contribute to AD and its symptoms. Cells of the immune system, called T cells, secrete messengers called cytokines and interleukins (IL) that tell other immune cells to get involved, leading to inflammation, signal structural cells of the skin (keratinocytes) to break down the skin barrier and even cause itch (Figure 1). The biologic dupilumab works to inhibit the activity of two key ILs in AD, IL-4 and IL-13. Now, several additional cytokines and ILs are also thought to play a role in AD — meaning more potential options for future biologic therapies.
Biologics: What are they and how can they improve treatment of eczema?
A biologic is a drug made from biological (living) sources like cells from humans, animals, plants, fungi or microbes. Biologic drugs are sometimes called “biologic response modifiers” because they change a process already occurring in cells or for a particular disease. In AD, new biologic drugs can modify the elevated immune response driving the disease.
Some people with AD can be treated with medications applied to the surface of the skin (topical medications) to ‘turn down’ inflammatory immune responses and control itch. Others have more severe disease that is resistant to topical treatments and need systemic (i.e. ‘whole-body’) types of medications to better control their AD and improve quality of life.
Traditional ‘whole-body’ systemic medications for AD include broadly immunosuppressive agents such as cyclosporine and methotrexate. Dupilumab is also considered a systemic agent, in that it acts on the whole body, but due to its ability to target only a specific component of the immune response (the IL-4 receptor alpha), it is not immunosuppressive and has offered a much needed new approach for the treatment of moderate-severe AD. Biologics for a number of immune-mediated diseases have offered a revolutionary way to more directly target key immune response pathways involved in disease, while leaving other immune responses unaffected. Biologics for diseases like psoriasis and asthma have been available since 2003 and provided clues about how a similar approach for AD could be possible.
A biologic, such as dupilumab, is made in a laboratory by cells that produce human monoclonal antibodies (mAb), a protein made up of amino acids. These mAb work similar to antibodies made by the body during an immune response to a virus or a bacteria, but instead of targeting the microbe, they can target specific immune cells or proteins in the body, bind to them tightly and prevent them from exerting their effects or even get rid of them. Currently, biologic mAb need to be injected in order to be effective, since taking them through the digestive system would disrupt their three-dimensional protein structure and render them unable to bind to their targets — much like a key needs to be a certain configuration to open a lock.
“Some biologics in early development can actually kill some of the inflammatory cells rather than making them quiet,” according to Dr. Eric Simpson of Oregon Health and Science University, and chair of NEA’s Research Advisory Committee, one of the clinical researchers working to take biologics for AD through clinical trials. “This could lead to prolonged remission times even after the drug is stopped, which is very exciting!”
A biologics revolution for AD treatment is on the way
Dr. Emma Guttman-Yassky, chair of dermatology and immunology at the Icahn School of Medicine at Mount Sinai in New York said, “This is a very exciting time for biologics in AD. Research into the immune mediators of AD opened doors to tremendous scientific development. It is a busy field of study. With AD there is a need to target different immune activities to achieve 100% clearance in all patients. Further, some of these biologics can also work for asthma.” Not only can AD differ from patient to patient depending upon age, race, whether the patient has a genetic mutation in filaggrin (causing skin barrier disruption) and other factors, response to treatments can also be variable2 — which is in part why treatment of AD is not a ‘one size fits all.’ The goal of having a myriad of options to treat moderate-severe AD, and eventually approach treating each patient’s disease in a more personalized way, is currently driving development of over 25 different biologic drugs with more than 10 unique IL and cytokine targets. Figure 1 shows many of these current drugs in development and which immune pathways they are intended to inhibit. Typically, only one out of several thousand drugs makes it through clinical trials, FDA approval and into use3 due to limited efficacy, side effects, inability to scale up production or drug instability among other reasons. Indeed biologics targeting IL-17C and IL-33 have been tried and failed in AD clinical studies, according to Dr. Simpson. However, several new biologics are showing promise in clinical trials, such as tralokinumab, lebrikizumab and nemolizumab, which are furthest along in development. Dr. Guttman-Yassky said, “Patients who do not respond to other drugs can use biologics as the first or second line of treatment.”
Tralokinumab (LEO Pharma) acts by targeting IL-13, which is one of the cytokines that tells other cells of the immune system to get involved in the inflammatory response. Two long-term Phase III studies (52 weeks) of safety and efficacy of tralokinumab for treating moderate-severe AD were published in 2020 with hundreds of adults (18 and older) in each study.4 Trials for treatment of adolescents and more long-term trials are currently being recruited.5 In the published studies, patients were treated with 300 mg of tralokinumab injected subcutaneously every two weeks. Researchers noted improvement in Investigator’s Global Assessment (IGA) and in the Eczema Area and Severity Index (EASI) by week 16 of treatment with tralokinumab compared to placebo, and these improvements continued for most patients through week 52. Improved sleep, itch and overall quality of life were noted for AD patients participating in the studies. Reported side effects included upper respiratory tract infections (common cold) and eye and skin infections, but for the most part these did not cause the patients to leave the study or quit taking tralokinumab.4 The majority of side effects happened during the first 16 weeks of treatment and did not continue as patients were on the drug for longer. FDA review of tralokinumab for moderate-severe AD is anticipated in the second quarter of 2021.
Lebrikizumab (Eli Lilly) also targets IL-13, preventing formation of the IL-13R alpha 1/IL-4R alphareceptor signaling complex. A Phase IIb study of safety and efficacy of lebrikizumab was published in 2020 with 280 adult AD patients split between the group who received the lebrikizumab and those who received the placebo.6 Phase III trials, long-term safety and efficacy studies and trials in adolescents (12 and older) are currently being recruited.5 In this published study, patients were injected subcutaneously with lebrikizumab at doses of 125 mg every four weeks, 250 mg every four weeks or 250 mg every two weeks. Improvement in the EASI score from the beginning of the study and 16 weeks was observed, as was lessening of itch as early as day two after the start of treatment. Side effects were injection site reactions, herpes virus infections and eye infections, but did not cause patients to leave the study.6
Nemolizumab (Galderma) targets the IL-31 receptor, which is a receptor on nerve cells and on immune cells called eosinophils that are activated by signals from T cells. Both eosinophils and nerve cells drive itch responses, and eosinophils also interfere with the ability of keratinocytes to maintain a good skin barrier. A Phase IIb study (24 weeks) of safety and efficacy of nemolizumab was published in 2020 with 226 patients split between those receiving placebo and those receiving 10 mg, 30 mg or 90 mg of the drug by subcutaneous injection every four weeks.7 All patients remained on their current topical steroid treatments during this study. Phase III trials and long-term trials are currently being recruited for nemolizumab.5 Researchers observed an improvement in the EASI score by week four of treatment, with the 30 mg dose being most effective. A decrease in itch was also observed during the study. The most common side effects were upper respiratory tract infection and infections/inflammation in the nose.7
The future: How can new biologics support the treatment revolution in AD?
Current clinical guidelines indicate the goal to manage AD with topical approaches first, if possible, before moving on to systemic treatments due to the increased risk for and severity of possible side effects.8–10 Patients and their healthcare providers should work together to review any factors, including the impact of the disease on a person’s quality of life, before deciding on the best systemic treatment option, including biologics.11
“We now have over four years of safety data for the first biologic (dupilumab), and there are no new side effects emerging. In fact patients continue to improve with longer-term use and experience fewer side effects over time,” said Dr. Simpson. “We are also seeing benefits beyond skin inflammation like improved mental health, reduced infections and reduced allergy symptoms for some patients. Biologics are not without risk and will likely need to be used in a continuous fashion. That said, I think as the new biologics come on board, we may see more potent responses and less frequent dosing like we see in psoriasis, where 80% of patients can get clear skin with dosing only every three months.”
While so far only dupilumab has been approved for children six years and older (with current trials being conducted for children six months to five years), there is also hope that some of the other biologics in development may also be able to be used as therapies for children and adolescents.12 Dr. Guttman-Yassky said, “This is a very exciting time for our patients with biologics changing the treatment paradigm. It is my hope to be able to treat children with AD with these biologics to really modify the disease even from the beginning.” As new research continues to shed light into the immunological complexity of AD, at different ages and with different racial backgrounds,13 the ability to target different and potentially multiple immune response pathways could improve treatment outcomes while minimizing treatment trial and error. Dr. Simpson aims higher. “Biologics that can cure the disease would be the holy grail,” he said, “and we are hoping this is a possibility in the future!”
Take Home Points:
Key Words to Know:
Figure 1: Illustration of the multiple immune pathways and targets
for biologics in atopic dermatitis. Shown is a representation of
the contributing genetic, environmental, skin, and immune system
contributors (Th cells e.g. Th1, Th2, Th17, Th22), B cells (B), eosinophils
(Eos), ILC2 cells (type 2 innate lymphoid cell), LC/IDEC (Langerhans
cells, inflammatory epidermal dendric cells) to the progression
and signs and symptoms of atopic dermatitis. Biologics such as
dupilumab and others in development (blue boxes) are shown in
relation to the specific immune component they inhibit, such as
interleukins (e.g. IL-4, IL-13), antibodies (i.e. IgE), or other cytokines (i.e.
TSLP (thymic stromal lymphopoietin)). Figure adapted from Reference 14.
1. Alexander H, Patton T, Jabbar-Lopez ZK, Manca A, Flohr C. Novel systemic therapies in atopic dermatitis: what do we need to fulfil the promise of a treatment revolution? F1000Res. 2019;8.
2. Brunner PM, Guttman-Yassky E, Leung DY. The immunology of atopic dermatitis and its reversibility with broad-spectrum and targeted therapies. J Allergy Clin Immunol. 2017;139(4S):S65-S76.
3. Brodniewicz T, Grynkiewicz G. Preclinical drug development. Acta Pol Pharm. 2010;67(6):578-585.
4. Wollenberg A, Blauvelt A, Guttman-Yassky E, et al. Tralokinumab for moderate-to-severe atopic dermatitis: results from two 52-week, randomized, double-blind, multicentre, placebo-controlled phase III trials (ECZTRA 1 and ECZTRA 2). Br J Dermatol. 2020.
5. www.clinicaltrials.gov. United States National Library of Medicine. Published 2021. Accessed February 13, 2021.
6. Guttman-Yassky E, Blauvelt A, Eichenfield LF, et al. Efficacy and Safety of Lebrikizumab, a High-Affinity Interleukin 13 Inhibitor, in Adults With Moderate to Severe Atopic Dermatitis: A Phase 2b Randomized Clinical Trial. JAMA Dermatol. 2020;156(4):411-420.
7. Silverberg JI, Pinter A, Pulka G, et al. Phase 2B randomized study of nemolizumab in adults with moderate-to-severe atopic dermatitis and severe pruritus. J Allergy Clin Immunol. 2020;145(1):173-182.
8. Boguniewicz M. Atopic dermatitis: the updated practice parameter and beyond. Allergy Asthma Proc. 2014;35(6):429-434.
9. Boguniewicz M, Fonacier L, Guttman-Yassky E, Ong PY, Silverberg J, Farrar JR. Atopic dermatitis yardstick: Practical recommendations for an evolving therapeutic landscape. Ann Allergy Asthma Immunol. 2018;120(1):10-22 e12.
10. Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies. J Am Acad Dermatol. 2014;71(1):116-132.
11. Simpson EL, Bruin-Weller M, Flohr C, et al. When does atopic dermatitis warrant systemic therapy? Recommendations from an expert panel of the International Eczema Council. J Am Acad Dermatol. 2017;77(4):623-633.
12. Scott JB, Paller AS. Biologics in pediatric psoriasis and atopic dermatitis: revolutionizing the treatment landscape. Cutis. 2020;106(5):224-226;E221;E222.
13. Brunner PM, Guttman-Yassky E. Racial differences in atopic dermatitis. Ann Allergy Asthma Immunol. 2019;122(5):449-455.
14. Chu CY. Treatments for Childhood Atopic Dermatitis: an Update on Emerging Therapies. Clin Rev Allergy Immunol. 2020.
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