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Atopic Dermatitis – Current State of Research on Biological Treatment

Barbara Klasa
Barbara Klasa
 and 
Ewa Cichocka-Jarosz
Ewa Cichocka-Jarosz
   | Jul 29, 2020
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Article Category: Review Paper
Published Online: Jul 29, 2020
Page range: 53 - 66
DOI: https://doi.org/10.34763/jmotherandchild.2020241.2003.0000010
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© 2020 Barbara Klasa et al., published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Figure 1

The pathomechanism of inflammation and current research directions for biological treatment of AD (courtesy of HL Nguyen, MM Tollefson, with permission from the Springer Nature publishing house) [10]
The pathomechanism of inflammation and current research directions for biological treatment of AD (courtesy of HL Nguyen, MM Tollefson, with permission from the Springer Nature publishing house) [10]

Characteristic changes in acute and chronic atopic dermatitis (AD)

Characteristic Exacerbation AD Chronic form AD
Th2 type activation pathway and related cytokines/chemokines Increased activity of IL-4, IL-13, IL-31 Increased activity of IL-5, IL-13, IL-31, IL-10, CCL5, CCL13, CCL18. Equivocal results for IL-4
Th22 type activation pathway and related cytokines Increased IL-22 activity Increased activity of IL-22, IL-32
Th1 type activation pathway and related cytokines/chemokines A slight increase in IFN-g, MX1, IL-1b, CXCL9-11, but not in all phenotypes Significant increase in IFNg, MX1 (markers associated with Th-1 cytokine), IL-1b, CXCL9-11
Th17 type activation pathway and related cytokines A slight increase in the level of IL-17, IL-23p19, IL-23p40 The level of activation is similar to that of acute AD
Infiltration of immune cells Infiltration of immune cells Intensification of changes as in the exacerbation
Epidermal changes Increased hyperplasia, epidermal thickening, marker proliferation (Ki67, K16, IL-22); reduction in the level of epidermal barrier proteins (involucrine, loricrin, filaggrin) Intensification of changes as in the exacerbation
Reduced expression of final protein and lipid differentiation Decreased expression of FLG, LOR, PPL and other differentiation proteins; significant lipid disorders Intensification of changes as in the exacerbation

Treatment depending on the severity of atopic dermatitis (AD)

Medication Mechanism of action Characteristics
AD: mild and moderate form
PDE-4 inhibitors
Crisaborole Inhibits the degradation of PDE4-dependent cyclic adenosine monophosphate, which in turn regulates T-cell signalling pathways, enhancing cellular control of inflammation. Topical drug – 2% ointment Phase IV studies in children between 3 and 24 months of age have been completed
RVT-501 Phosphodiesterase 4 Inhibitors (PDE4i). Topical drug – 0.5% ointment Phase II studies in children aged between 2 and 17 years have been completed.
Inhibitors JAK-STAT
Tofacitinib Blocking the cell signal transduction pathway inhibits pro-inflammatory cytokines In the treatment of AD, it has so far only been tested in adults
AD: moderate and severe form
Inhibitors JAK-STAT
Baricitinib Inhibitor JAK1/JAK2 – oral drug All patients included in this study used local GCS 1 month before starting baricitinib therapy, therefore the efficacy of baricitinib monotherapy is unknown
Upadacitinib Inhibitor JAK1 – oral drug Currently in the research phase in children aged from 2 to 17 years and adults with AD.
Abrocitinib (Pf-04965842) Inhibitor JAK1 – oral drug Currently in phase III studies assessing the effectiveness of the drug in adolescents aged >12 years
Ruxolitinib Inhibitor JAK1/JAK2 – topical drug Initially used to treat myelofibrosis and true polycythaemia, it is currently studied in children aged between 12 and 17 years and adults with AD
ASN002 Inhibitor JAK/TYK2/SYK – oral drug Phase IIa studies in adults aged between 18 and 75 years have been completed.
Delegocitinib Inhibitor JAK/TYK2 – topical drug Examined in children aged from 12 to 17 years and adults with AD.
Phosphodiesterase 4 Inhibitors (PDE4i)
Roflumilast Inhibitor PDE4 – topical drug Until present, tested only in adults – phase IIa studies showed no improvement after using 0.5% cream Roflumilast
Apremilast Inhibitor PDE4 – oral drug Positive results in the treatment of children and adults with refractory AD. High frequency of undesirable activities in the form of cellulitis. No further studies are planned due to the risk and benefit analysis
CRTH2 receptor antagonists
Fevipiprant/Timapiprant The antagonism on the CRTH2 receptor suppresses the formation of the inflammatory process Clinical studies have not demonstrated efficacy of the drug relative to placebo (NCT01785602, NCT02002208)
Thymus stromal lymphopoietin (TSLP) and OX40 inhibitors
GBR-830 Inhibitor TSLP (TSLP induces immune cells to produce pro-inflammatory cytokines). Anti-OX40 monoclonal antibody Phase II is completed in adults
Tezepelumab Inhibitor TSLP. Anti-TSLP monoclonal antibody To date, studies only in adults – phase IIa studies lack satisfactory results
(TAMA) therapeutic aryl hydrocarbon receptor modulating agent (AhR)
Tapinarof TAMA Tested in children aged 12–17 years and adults. Phase III research scheduled for 2019
Inhibitors IL-4/IL-13
Dupilumab Human monoclonal antibody blocking a subunit, common to IL-4 (IL-4Ra) and IL-13 receptors To date, dupilumab (Dupixent) has been studied in >7,000 patients aged >12 years, in >30 clinical trials giving very good treatment results (description in the text)
Pitrakinra IL-4 mutein – binds the IL-4Ra receptor by inhibiting the production of IL-4 and IL-13 Phase II clinical trials in adults have been completed
Tralokinumab/Lebrikizumab Anti-IL-13 monoclonal antibody Lebrikizumab and tralokinumab are undergoing phase III studies
Inhibitors IL-5
Mepolizumab Anti-IL-5 monoclonal antibody inhibits eosinophil activity Two clinical trials in adults with AD have been unsuccessful
Inhibitors IL-22
Fezakinumab Anti-IL-22 monoclonal antibody Phase IIa studies have shown that this medicine has little potential to treat AD
Inhibitors IL-12/IL-23 Ustekinumab Anti-IL-12/IL-23 monoclonal antibody The results of phase IIa studies are not convincing
Inhibitors IL-31/IL-31Ra
Nemolizumab IL-31Ra monoclonal antibody Phase I studies showed a significant reduction of pruritus and phase II studies evaluated the safety and tolerability of the drug. These studies showed that treatment with nemolizumab is well tolerated and it reduces the severity of pruritus, dermatitis and sleep disorders compared with placebo
BMS-981164 Monoclonal antibody IL-31 Phase I studies in 2015 – no results have been published so far
Neurokinin-1 Receptor Antagonists (NK1RA)
Serlopitant NK1R antagonist – oral drug Effective in the treatment of chronic pruritus in adults; however, phase II drug research in patients with AD did not bring satisfactory results
Tradipitant NK1R antagonist – oral drug Phase III drug research is currently underway
K-Opioid Receptor Agonists (KOR)
Asimadoline Agonist KOR – oral drug Phase II drug studies have been completed. Effective in reducing itching at night
Histamin Receptor Antagonists-4 (H4R)
ZPL-389 Antagonist H4R Studies in adults only. The advantage over placebo has not been demonstrated. Phase IIB study is currently underway
Immunoglobulin E (IgE) inhibitors
Omalizumab Anti-IgE monoclonal antibody There are no satisfactory treatment effects in patients with AD. A drug used to treat asthma
Ligelizumab Anti-IgE monoclonal antibody Higher affinity for IgE than omalizumab. Phase II RCT completed

List of clinical trials conducted for biological drugs in atopic dermatitis (AD)

Medication Target Study phase Manufacturer www.ClinicalTrials.gov Target endotype AD phenotype
Dupilumab Dupixent IL-4Ra Approved by FDA 2017 – adults, FDA 2019 – adolescents EMA – 2019 Sanofi-Aventis Groupe, Paris NCT01949311Phase III in progress – patients>18 years oldNCT02407756Phase II completed – in children12–18 years old, moderate and severe ADNCT02612454Phase III in progress – in children36 months–18 years oldNCT03054428Phase III completed – patients>12–18 years oldNCT02407756Phase II completedPatients 36 to <18 years oldNCT02612454Phase IIIPatients 36 months old–<18 years oldNCT03411837Phase IVPatients 312 years oldNCT03428646Observation of patients receiving DupixentPatients 312 years oldNCT03549416New systemic treatment options in patients with AD, including dupilumab (conjunctivitis during dupilumab treatment)Patients: children, adults Th2/Tc2 All AD phenotypes
Pitakinra/Aeroderm IL-4 Phase II completed Aerovance, Berkeley, CA NCT00676884Patients >18 years old Th2/Tc2 All AD phenotypes
Mepolizumab IL-5 Phase II completed Glaxo SmithKline, Research Triangle Park, NC NCT03055195Patients >18 years old Th2/Tc2 AD with elevated eosinophils
Tralokinumab IL-13 Phase II completed MedImmune, Gaithersburg, MD NCT02347176Patients >18 years old Th2/Tc2 All AD phenotypes
Lebrikizumab IL-13 Phase II completedPhase III Hoffman-LaRoche, Basel, Switzerland NCT02340234NCT02465606NCT03443024Patients >18 years oldNCT04250337, NCT04250350Patients 12–17 years old active Th2/Tc2 All AD phenotypes
QAW039/Fevipiprant CRTH2 Phase II completed (drug development programme stopped) Novartis, Basel, Switzerland NCT01785602Patients >18 years old Th2/Tc2 All AD phenotypes
OC000459 CRTH2 Phase II completed (drug development programme stopped) Atopix, Carlsbad, CA NCT02002208Patients >18 years old Th2/Tc2 All AD phenotypes
AMG157/tezepelumab TSLP Phase I completed Amgen, Newbury Park, CA NCT00757042Patients >18 years old Th2/Tc2, Th17 All AD phenotypes, prevention of allergic march
MK-8226 TSLPR Phase I completed Merck, White-house Station, NJ NCT01732510Patients >18 years old Th2/Tc2, Th17 All AD phenotypes, prevention of allergic march
GBR830 OX40 Phase I completed Glenmark, Mumbai, India NCT02683928Patients >18 years old Th2/Tc2 All AD phenotypes
KHK4083 OX40 Phase I completed Kyowa HAkko Kirin, Otemachu, Japan NCT03096223Patients >18 years old Th2/Tc2 All AD phenotypes
QGE031 IgE Phase II completed Novartis NCT01552629Patients >18 years old Allergic sensitization Extrinsic AD, AD in African Americans, AD in Asians, childhood AD
Tofacitinib JAK1/3 Phase II completed Innovaderm, Montreal, Quebec, Canada NCT02001181Patients >18 years old Th1, Th2, Th22, IFN-a, IgE class – keratinocyte modulation pruritus differentiation All AD phenotypes
Baricitinib (LY3009104) JAK1/2 Phase II completed Eli Lilly, India-napolis, IN NCT02576938Patients >18 years old Th1, Th2, Th22, IFN-a, IgE class – keratinocyte modulation pruritus differentiation All AD phenotypes
Upadacitinib (ABT-494) JAK1 Phase II completed AbbVie, Lake Bluff, IL NCT02925117Patients >18 years old Th1, Th2, Th22, IFN-a, IgE class – keratinocyte modulation pruritus differentiation All AD phenotypes
ASN002 JAK/SYK Phase II completed Asana BioSciences, Lawrenceville, NJ NCT03531957Patients >18 years old Th1, Th2, Th22, IFN-a, IgE class – keratinocyte modulation pruritus differentiation + Th17 All AD phenotypes
PF-04965842 JAK1 Phase III completed Pfizer, New York, NY NCT03349060Patients >12 years old Th1, Th2, Th22, IFN-a, IgE class – keratinocyte modulation pruritus differentiation All AD phenotypes
Crisaborole/Eucrisa Staquis PDE4 Approved by FDA 2016 >2 yearsFDA 2020 >3 monthsEMA 2020 >2 years Pfizer Labs, NY; Pfizer Europe, MA EEIG NCT02118766NCT02118792Phase II completed in children>2 years old Anti-inflammatory drugs (NSAIDs) All AD phenotypes
Roflumilast PDE4 Phase II completed AstraZeneca, Cambridge, UK NCT01856764Patients >18 years old Anti-inflammatory drugs (NSAIDs) All AD phenotypes
RVT-501 PDE4 Active phase I Dermavant Sciences, Phoenix, AZ NCT03415282Patients >2–11 years old Anti-inflammatory drugs (NSAIDs) All AD phenotypes
Apremilast/Otezla PDE4 Phase II completed (drug development programme stopped) Celgene, Summit, NJ NCT02087943Patients >18 years old Anti-inflammatory drugs (NSAIDs) All AD phenotypes
Ustekinumab/Stelara IL-12/23p40 Phase II completed Janssen, Beerse, Belgium NCT01806662Patients >18 years old Th17, Th1, Th22 Intrinsic AD, AD in Asians, childhoodAD, EA in patients with chronic AD
CIM331/nemolizumab IL-31R Phase II completed Chugai, Tokyo, Japan NCT01986933Patients >18 years old Pruritus/Th2 All AD phenotypes
BMS-981164 IL-31 Phase I completed Bristol-Myers Squibb, New York, NY NCT01614756Patients >18 years old Pruritus/Th2 All AD phenotypes
ILV-094/Fezakinumab IL-22 Phase II completed Pfizer NCT01941537Patients >18 years old Th22, Th17 Intrinsic AD, AD in Asians, adult EA patients with AD, African American
Secukinumab/Cosentyx IL-17A Phase II completed Novartis NCT02594098Patients >18 years old Th17 (and IL-22) Intrinsic AD, AD in Asians, children and young adults from AD
MOR106 IL-17C Active phase II Galapagos NV, Mechelen, Belgium NCT03568071Patients >18 years old Th17 Intrinsic AD, AD in Asians, children and young adults from AD

Strategy for gradual treatment of atopic dermatitis (AD)

Chronic treatment Treatment of exacerbations (often recommended in a hospital setting)
Severity IIISCORAD3 50

1st line: dupilumab, cyclosporin A, phototherapy (in selected cases)

2nd line: methotrexate, azathioprine

Periodic intensification of basic treatment such as emollient for the skin under a wet dressing

Intensification of basic treatment such as emollient for the skin under a moist dressing

Systemic glucocorticosteroid (GCS) (short – maximum up to 14 days) and/or local GCS daily all over the skin (possibly for several under the dressing)

Limitation of pyodermisation

 Antibiotic in general (first generation cephalosporins or clindamycin preferred)

Antibiotic topically (fusidic acid, mupirocin, retapamulin)

Mupirocin locally on the skin of the atrium of the nose in attempts to eradicate the carrier of S. aureus

Disinfectants (polidocanol, octenidine, chlorhexidine, triclosan, KMnO4) and desiccants (tannin preparations)

Herpes infection

Acyclovir and observation in a hospital setting

Yeast or dermatophyte infection

Consider systemic treatment with imidazole derivatives (fluconazole >1 year old, itraconazole >12 years old), miconazole, terbinafine

Molluscum contagiosum infection – usually self-limiting

Technological fabrics with silver ions in some patients
Severity IISCORAD3 25–49

Local GCS with weak to moderate proactive strength

Proactive calcineurin (Protopic, Elidel) or PhD4 (Eucrisa) topical inhibitors

Periodic intensification of basic treatment such as emollient for the skin under a wet dressing
Severity ISCORAD < 25

Local GCS with weak proactive strength

Topical calcineurin inhibitors (Elidel) proactively or PhD4 (Eucrisa)
Basic treatment for all levels of severity AD

Avoiding irritants (e.g. rough fabrics) and aggravating (sweating, overheating, stress)

Dermocosmetics for washing the skin

Emollients 3 2 times per day used generously (after washing according to the principle of up to 5 min)

Elimination diet in justified cases

Probiotics with documented effects

Symptomatic antipruritic drugs
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