Atopic Dermatitis – Current State of Research on Biological Treatment

Klasa, Barbara; Cichocka-Jarosz, Ewa

doi:10.34763/jmotherandchild.2020241.2003.0000010

Figures & Tables

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

Atopic Dermatitis – Current State of Research on Biological Treatment

Figures & Tables

Figure 1

Characteristic changes in acute and chronic atopic dermatitis (AD)

Treatment depending on the severity of atopic dermatitis (AD)

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

Strategy for gradual treatment of atopic dermatitis (AD)

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