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Emerging Targeted Treatments


Key points

  • This chapter provides an overview of the pathogenesis of atopic dermatitis and the key mediators that are of therapeutic interest.

  • As we acquire more knowledge into the pathogenesis of atopic dermatitis, we will be able to use more targeted treatments

  • The two most recently Food and Drug Administration–approved medications are dupilumab and crisaborole.

  • There are a number of topical and systemic novel and emerging targeted therapies for atopic dermatitis.

  • Despite promise of these new drug therapies, potential gaps include limited head-to-head trials, lack of subgroup analysis, and high cost.

Introduction

This chapter is intended to discuss novel and emerging pharmaceutic treatments for patients affected by atopic dermatitis (AD). It will give a brief overview of the proposed mechanism of each treatment, the major side effects, and the most recent clinical data from trials and studies. We hope to provide a comprehensive overview of the new treatments available for AD and to make clinicians better informed about the particular strengths and weaknesses of each drug. It should also be noted that many of these treatments are still in development and may not be available for clinical use, and we encourage readers to follow up on the updated results of the trials and studies listed throughout each section. A summary of the medications can be found in Table 23.1 .

Table 23.1
List of targeted treatment options for atopic dermatitis
Name Topical/systemic Manufacturer Result Phase Major adverse events
Dupilumab Systemic Regeneron Favorable Conjunctivitis, keratitis, nasopharyngitis
Tralokinumab Systemic AstraZeneca Favorable 3 Upper respiratory tract infection (URTI), headache
Lebrikizumab Systemic Dermira/Eli Lilly Favorable 3 URTI, headache, nasopharyngitis
Omalizumab Systemic Novartis Variable N/A Injection site reaction, URTI, malignancies
Ligelizumab Systemic Novartis Unfavorable 2 Injection site reaction, URTI
Rituximab Systemic Genentech Biogen Unfavorable N/A
Nemolizumab Systemic Galderma Favorable 3 Nasopharyngitis, URTI, asthma-related exacerbations
Tofacitinib Systemic Pfizer Favorable 2 Neutropenia, lymphopenia, herpes-zoster-associated encephalitis, appendicitis, pericoronitis, skin infection
Barticitinib Systemic Eli Lilly Favorable 2 Neutropenia, lymphopenia, herpes-zoster-associated encephalitis, appendicitis, pericoronitis, skin infection
Abrocitinib Systemic Pfizer Favorable 3 Neutropenia, lymphopenia, herpes-zoster-associated encephalitis, appendicitis, pericoronitis, skin infection
Upadacitinib Systemic AbbVie Favorable 3 Infection, neutropenia, hepatic disorder, URTI, acne, headache, nasopharyngitis, diarrhea
Gusacitinib Systemic Asana Biosciences Favorable 2 Neutropenia, lymphopenia, herpes-zoster-associated encephalitis, appendicitis, pericoronitis, skin infection
Delgococitinib Topical LEO Pharma Favorable 2 Infection, neutropenia, URTI, acne, nasopharyngitis, hepatic disorder
Tacrolimus Topical Accord Healthcare Variable Skin infection, application pain
Pimecrolimus Topical Novartis Variable Skin infection, application pain
Crisaborole Systemic Pfizer Favorable Application pain
Apremilast Systemic Celgene Favorable 2 Diarrhea, weight loss
Ustekinumab Systemic Janssen Biotech Inc. Favorable 2 Infusion reaction, nasopharyngitis, URTI, malignancies
Risankizumab Systemic AbbVie Favorable 2 URTI
Secukinumab Systemic Novartis Favorable 2 Nasopharyngitis, hypertension
Fezakinumab Systemic Pfizer Favorable 2 URTI
Asimadoline Systemic Tioga Pharmaceuticals 2 N/A
Tapinarof Topical Dermavant Sciences Favorable 2 Folliculitis, contact dermatitis
JNJ 39758979 Systemic Janssen Biotech Inc. Unfavorable 2 Neutropenia
Adriforant Systemic Novartis 2 N/A
DS107 Topical, Systemic DS Biopharma Favorable 2 N/A
Aprepitant Systemic Merck Ltd. Unfavorable Leukopenia, hypotension
Serlopitant Systemic Menlo Therapeutics Unfavorable 2 Nasopharyngitis, URTI
Rosiglitazone Systemic GlaxoSmithKline Favorable N/A Weight gain
N/A , Complete data not available yet to fully access side effect profile.

Pathogenesis

Sustained barrier defects generated by filaggrin mutations, decreased ceramide synthesis, scratching, increased serine protease activity, and prolonged exposure to reduced environmental humidity result in epidermal dysfunction and allow for penetration of allergens found in pollen, microbes, and food ( ). In response to allergens, trauma, and inflammation, keratinocytes release inflammatory mediators such as interleukin-25 (IL25), IL33, thymic stromal lymphopoietin (TSLP), and pollen-associated lipid mediators (PALMs), which, along with presentation of allergens by dendritic cells, stimulate a T helper type 2 (Th2)-driven immune response ( ). TSLP receptor activates STAT1, STAT3, STAT5/JAK1, and JAK2, which are important for Th2 cell differentiation ( ).

These Th2 cells subsequently produce cytokines and chemokines, including IL4, IL5, IL13, and tumor necrosis factor-α (TNF-α), which stimulate B-cell class switching, immunoglobulin E (IgE) production, and eosinophil survival; induce proliferation of leukocyte adhesion molecules; and direct circulating lymphocytes, macrophages, and eosinophils to cutaneous sites of inflammation ( ). IL4 has been strongly associated with AD and requires numerous agents in the JAK-STAT pathway, including JAK1, JAK3, STAT3, STAT5, and STAT6 to enact its effects ( ). IgE contributes to AD pathogenesis through mast cell activation and subsequent release of preformed mediators such as histamine, IL4, and IL13, as well as through increased expression of FCεRI on Langerhans and dendritic cells, which results in further Th2 activation ( ). Mast cells also stimulate further IgE synthesis by B cells, upregulate integrins on Langerhans cells, and suppress IL12 production by dendritic cells, leading to polarization to the Th2 subtype ( ). Th2 cells also release IL31, which has been associated with higher disease severity, pruritus, chemotaxis of inflammatory cells, and induction of proinflammatory molecules by eosinophils through the JAK-STAT pathway ( ). Eosinophils release various cytokines and chemokines such as IL16, IL12, transforming growth factor-β (TGF-β), and IL13 ( ). The JAK-STAT pathway, through STAT6-mediated gene regulation, also stimulates B-cell differentiation, IgE class switching, and major histocompatibility complex (MHC) class II production ( ).

Similar to the JAK-STAT pathway, JAK-spleen tyrosine kinase (SYK) pathways have also been associated with AD pathogenesis by mediating IL17R-proximal signaling complex formation, which is responsible for upregulation of CCL20 in keratinocytes ( ). CCL20 has been found to attract immature dendritic cells and effector T cells into the dermis of inflamed skin ( ). SYK activation has also been implicated in B-cell survival, degranulation of mast cells, antigen presentation in dendritic cells, and proinflammatory cytokine production by macrophages ( ).

Th17 cells have also been implicated in the pathogenesis of AD as an enhancer, and an increased percentage of Th17 in blood correlates with the severity of AD ( ). Th17 cells release IL17, which enters the inflamed dermis and stimulates keratinocytes to produce proinflammatory cytokines and chemokines, including GM-CSF, TNF-α, IL8, and CXCL10 ( ). Patients with chronic AD have also been found to have increased blood levels of IL22-producing T cells ( ). IL22 induces keratinocyte proliferation and epidermal proliferation, and increased levels of IL22 are correlated with AD disease severity ( ).

Phosphodiesterase (PDE) functions to hydrolyze cyclic adenosine monophosphate (cAMP), and higher levels of PDE activity have been associated with increased IgE synthesis and IL4 production ( ). Increased PDE activity is seen in leukocytes of patients with AD and is thought to contribute to increased serum levels of IL10 and prostaglandin E2 ( ). IL12, which is stimulated by Th2-type cells, is thought to polarize naïve T cells to Th1-type cells and terminate Th2-type cytokine patterns ( ). A switch from Th2 cells to a predominantly Th1 cell response has been associated in the chronic and late phases of AD ( ). Increased levels of IL12, mRNA, and interferon-gamma (IFN-γ) (which are produced by Th1 cells) in AD lesions have also been linked to chronic AD ( ).

Pruritus in AD is caused by numerous mediators, including histamine, neuropeptides, neurotransmitters, cytokines, proteinases, and arachidonic acid derivatives ( ). Histamine induces IL13 and IL31 production and activates sensory neurons, primarily through histamine-1 receptors (H 1 R) and histamine-4 receptors (H 4 R) ( ). Through H 4 R, histamine also activates mast cells, basophils, and eosinophils ( ). One potent releaser of histamine from mast cells is compound 48/80, which, upon injection, has been shown to cause itching in mice ( ). Similarly, increased concentrations of substance P, a neuropeptide that induces itching through neurokinin receptors (NK1R,) and neuropeptide Y are present in patients with AD ( ).

Peroxisome proliferator-activated receptor gamma (PPAR-γ) is a type of nuclear receptor that has an increased expression in the monocytes and T lymphocytes of AD patients and is responsible for keratinocyte differentiation and permeability barrier homeostasis ( ).

Dihomo-γ-linolenic acid (DGLA) is a fatty acid that has been found to be significantly lower in the serum of patients with AD than in healthy volunteers ( ). DGLA is also metabolized into antiinflammatory eicosanoids, and oral administration of DGLA in mice prevents the development of AD by suppressing the activation of mast cells and keratinocytes ( ).

Recalcitrant and moderate to severe AD often require systemic treatment. Immunosuppressants such as methotrexate, cyclosporine A, mycophenolate mofetil, and azathioprine have traditionally been used; however, significant side effect profiles can limit their long-term use. Newer immunomodulators (i.e., biologics and small-molecule inhibitors) selectively target specific cytokines and regulators involved in AD pathogenesis and have much more desirable side effect profiles.

Currently, the only Food and Drug Administration (FDA)–approved biologic medications for AD are dupilumab and crisaborole. There are a number of new and promising treatments currently under investigation. This chapter provides a summary and review of systemic therapies that target specific mediators involved in the pathogenesis of AD and its related symptoms. Included are those therapies that have been specifically approved for AD, those undergoing clinical trials, and those that have demonstrated efficacy to a significant degree.

Treatments targeting pathogenic cytokines

Anti-IL4

Dupilumab is currently the only FDA-approved systemic immunomodulator indicated for AD. It is fully a monoclonal antibody that inhibits IL4 and IL13 receptors by binding to the α-subunit shared by these receptors ( ). In two phase 3, randomized, double-blind, placebo-controlled, parallel-group trials of identical design involving a total of 1379 adults with moderate to severe AD refractory to topical treatment, significantly more patients who received dupilumab 300 mg subcutaneously every other week for 16 weeks reached the primary endpoint of an Investigator Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) (38% and 36% for the dupilumab group vs. 10% and 8% for the placebo group, P < .001 for both comparisons vs. placebo) ( ). Furthermore, an improvement of 75% or more on Eczema Area and Severity Index (EASI-75) (which measures erythema, induration, papulation, and edema; excoriations, and lichenification) was achieved by significantly more patients who received dupilumab compared to patients receiving placebo (51% and 44% for the dupilumab group vs. 15% and 12% for the placebo group, P < .001 for both groups compared to placebo). Additionally, patients who completed this trial were able to enter an ongoing maintenance trial, a phase 3, randomized, double-blind, placebo-controlled, parallel-group trial involving 422 patients who were rerandomized in a 2:1:1:1 ratio to receive their original regimen of 300 mg dupilumab weekly or every 2 weeks, a less frequent regimen of 300 mg every 4 or 8 weeks, or placebo for 36 weeks ( ). More patients who continued to receive dupilumab every week or every 2 weeks maintained EASI-75 response compared to those taking dupilumab every 4 weeks, 8 weeks, or placebo (71.6%, 58.3%, 54.9%, 30.4%, respectively; P < .001) ( ). A phase 3, nonrandomized, open-label, single-group assignment of dupilumab in adult patients who have participated in previous dupilumab clinical trials is currently ongoing ( ). In terms of side effects, dupilumab has been associated with an increased incidence of ocular surface diseases such as conjunctivitis and keratitis ( ).

Anti-IL13

Tralokinumab is a fully monoclonal IgG4 monoclonal antibody that binds to and neutralizes the effects of IL13 via inhibition of signal transduction ( ). In a phase 2b, randomized, double-blinded, placebo-controlled, parallel assignment, dose-ranging study involving 204 adults with moderate to severe AD lasting longer than 1 year, participants were randomized in a 1:1:1:1 ratio to receive placebo or tralokinumab (45, 150, or 300 mg) subcutaneously every 2 weeks for 12 weeks, with a 10-week follow-up period ( ). At 12 weeks, more patients who were treated with 300 mg of tralokinumab were found to have a significantly improved change in EASI score compared to patients who received placebo (adjusted mean difference = −4.94, P = .01). Additionally, improvements in IGA response rates were associated with increasing doses of tralokinumab, with the greatest absolute percentage difference from placebo being observed in participants who received 300 mg of tralokinumab (26.7% vs. 11.8%, P = .06). Patients treated with 300 mg of tralokinumab also had significant improvements in SCORAD, Dermatology Life Quality Index, and pruritus numeric rating scale versus placebo. Two randomized, double-blind, placebo-controlled, parallel assignment, phase 3 clinical trials involving 780 patients being given tralokinumab and/or placebo for 52 weeks are currently ongoing or completed, but results are not yet available ( ).

Lebrikizumab is a humanized monoclonal antibody that binds to IL13 and inhibits signal transduction by blocking IL13α1/IL4Rα heterodimerization ( ). In a randomized, placebo-controlled, double-blind, phase 2 study of 209 adults with moderate to severe AD who were treated with lebrikizumab 125 mg single dose, lebrikizumab 250 mg single dose, lebrikizumab 125 mg every 4 weeks for 12 weeks, or placebo every 4 weeks for 12 weeks, significantly more patients treated with lebrikizumab 125 mg every 4 weeks achieved EASI-50 at week 12 of the study compared to patients receiving placebo every 4 weeks (82.4% vs. 62.3%, P = .26) ( ). Additionally, the percentage of patients who achieved an IGA of 0 or 1 and the number of patients with SCORAD-50 was higher at week 12 in all lebrikizumab groups compared with placebo. A phase 2, randomized, double-blind, placebo-controlled, dose-ranging trial for lebrikizumab in 280 adult patients with moderate to severe atopic eczema lasting longer than 1 year was completed in 2019, but results are not yet available ( ). Two phase 3, randomized, double-blind, placebo-controlled, parallel-group studies involving 400 child and adult patients with moderate to severe AD being treated with lebrikizumab monotherapy are currently recruiting and are expected to be completed in 2021 ( ).

Anti-IL31

Nemolizumab is a humanized monoclonal antibody against IL34 receptor A and inhibits signaling of IL31, which plays a role in pruritus ( ). In a phase 2, randomized, double-blind, placebo-controlled, multicenter, 12-week trial of 264 adults with moderate to severe AD refractory to topical glucocorticoids or topical calcineurin inhibitors who were given subcutaneous nemolizumab at a dose of 0.1 mg, 0.5 mg, or 2 mg per kilogram of body weight, or placebo every 4 weeks, or 2 mg nemolizumab/kg every 8 weeks with placebo given at week 4, there was significant dose-dependent reduction in pruritus from baseline as measured by the pruritus visual-analogue scale (VAS); reductions of 43.7%, 59.8%, and 63.1% were seen in the 0.1 mg/kg, 0.5 mg/kg, and 2.0 mg/kg groups, respectively, compared to a 20.9% reduction seen with the placebo ( P = .002, P < .001, P < .001) ( ). Participants treated with nemolizumab also experienced significant reductions in pruritus verbal rating scale, improvements in EASI score and SCORAD, and improvements in mean percentage changes from baseline in sleep disturbance-VAS (−52.3%, −59.1%, and −62.6% for 0.1 mg/kg, 0.5 mg/kg, and 2.0 mg/kg vs. –31.9% with placebo). A follow-up study in which patients continued their previous nemolizumab dose every 4 weeks or every 8 weeks for 52 weeks in a double-blind extension found that there were maintained or decreased pruritus VAS scores from week 12 to week 64 in patients randomized to receive nemolizumab, with the greatest improvement occurring in the 0.5 mg/kg group ( ). Mean percentage change from baseline in EASI score, SCORAD score, and sleep disturbance-VAS scores were also maintained or decreased from week 12 to week 64. Patients who received placebo in the previous study and switched to nemolizumab at week 12 experienced a favorable response to treatment in pruritus VAS score by week 16 and maintained this response through week 64. A phase 2, randomized, double-blind, multicenter, parallel-group, placebo-controlled, dose-ranging study of 351 adults with moderate to severe AD who were randomized into a nemolizumab 10 mg group, nemolizumab 30 mg group, nemolizumab 90 mg group, and a placebo group found that percent change from baseline in EASI at week 24 was −72.2%, −73.4%, −69.2%, and −58.4%, respectively, and demonstrated reductions in EASI scores that were statistically significant for nemolizumab compared to placebo for the 10 mg and 30 mg treatment groups ( P = .051, P = .016), but not for the 90 mg treatment group ( P = .322) ( ). A phase 2, multicenter, open-label, single-group clinical trial to assess the safety of nemolizumab in adolescents with AD is currently recruiting ( ).

Anti-IL12/23

Ustekinumab, which is approved for the treatment of plaque psoriasis, is a fully humanized monoclonal antibody that neutralizes IL12 and IL23 by targeting the shared p40 subunit, causing regulation of Th1 and Th17/Th22 responses ( ). In a phase 2, double-blinded, placebo-controlled, crossover study of 32 adult patients with moderate to severe chronic AD who were given subcutaneous ustekinumab (45 mg and 90 mg per injection for patients weighing <100 kg or >100 kg, respectively) or placebo at weeks 0, 4, and 16 with a crossover at weeks 16, 20, and 32, for 40 weeks, the ustekinumab group achieved higher SCORAD50 response at 12 weeks, 16 weeks, and 20 weeks compared to placebo, but the difference was not statistically significant ( ). In a phase 2, randomized, double-blind, placebo-controlled, multicenter, parallel-group study of 79 adult Japanese patients with severe or very severe AD who were given 45 mg or 90 mg ustekinumab or placebo subcutaneous injections at 0 weeks and 4 weeks with a primary efficacy endpoint in percent change from baseline in EASI score at week 12, ustekinumab treatment demonstrated nonsignificant improvement in least-square mean change from baseline EASI score at week 12 (45 mg: −38.2, P < .95; 90 mg: −39.8%, P < .81; vs. placebo: −37.5%) and nonsignificant improvements in IGA, EASI-50, and EASI-75 ( ).

Risankisumab is another anti-IL23 humanized IgG monoclonal antibody that has been approved by several countries for treatment of moderate to severe plaque psoriasis ( ). A phase 2, multicenter, randomized, double-blinded, placebo-controlled, parallel assignment study of 155 children and older adults with moderate to severe AD receiving double-blind placebo for 16 weeks followed by risankizumab dose 1 or 2 for 24 weeks is currently ongoing and is estimated to be completed in April 2021 ( ).

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