Innovación en dermatitis atópica: De la fisiopatología al

tratamientoJosé Manuel Carrascosa

Servei de Dermatología

UAB- IGTP

Hospital Universitari Germans Trias i Pujol

Badalona

Conflictos de interés

• He participado como PI/SI, recibido honorarios como ponente invitado, miembro de steering comitee, advisor para Sanofi, Lilly, Abbvie, Pfizer, Leo-Pharma, UCB

Dermatitis atópica

• La dermatosis inflamatoria másprevalente en el mundo ( 15-20% a lo largo de la vida ).

• 230 millones de pacientes en todo el mundo.

• Más prevalente en la infancia, perotambién frecuente en el adulto.

• Heterogeneidad clínica/ genética / fenotípica.

• Presumible complejidad/ heterogeneidad patogénica.

Dermatitis atópica: la nueva frontera

Dermatitis atópica: “outside-in” o “inside-out” ?

Función barrera y DA

• Alteraciones en filagrina, loricrina e involucrina.

• Alteración en tight junctions.

Filagrina y riesgo de DA: ¿heredado o adquirido ?

• La ausencia del gen de la filagrina (es decir, una mutación nula FLG) se asocia con un riesgo para el inicio más temprano de la DA, así como para la enfermedad más grave y persistente.

• Los pacientes con una mutación nula FLG tienen 1.2 a 13 veces el riesgo de desarrollar AD.

• Sin embargo, aproximadamente el 40% de los individuos con alelos nulos FLG no desarrollan AD.

Howell MD, Kim BE, Gao P, et al. Cytokine modulation of atopicdermatitis filaggrin skin expression. J Allergy Clin Immunol. 2009;124(3 suppl 2):R7-R12.

Kong et al. Genome Res 2012

Decreased diversity of Cutaneous

microbiota in AD

Lesional skin: S aureus ,S.epidermidis

Propionibacterium, Corynebacterium,Streptococcus SA

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S.Aureus and AD

• ~90% of AD patients are colonized with S. aureus in the lesional skin whereas thegreat majority of healthy individuals do not harbor the bacterium in the skin

• S. aureus loads in the affected skin correlate withdisease flares

• the role of S. aureus is causative in AD remains to be determined.

Reversibilidad de la DA con tratamientos frente la inflamación: ¿ la prueba de una enfermedad : “inside-out” ?

Therapy with IL4 y IL13 induce modifications in the barrierfunction independently of FLG mutations.

Los pacientes con AD pueden desarrollar un defecto "adquirido" en la expresión de filagrina en presencia de una respuesta inflamatoria atópica (IL-4 / IL13)

Inmunología en DA: inmunidad innata

• Mutaciones en TLT y NOD-like receptors

• Disminución de AMP

( catelicidina y b-defensinas)

Inmunología en DA: LC, iDEC y patron Th2

AD=atopic dermatitis; AMP=antimicrobial peptide; DC=dendritic cell; EOS=eosinophil; iDEC=inflammatory dendritic epidermal cell; IL=interleukin; LC=Langerhans cell; MC=mast cell; pDC=plasmacytoid dendritic cells; Tc=cytotoxic T cell; TEM=effector memory T cell; Th=T helper cell; TSLP=thymic stromal lymphopoietin; Guttman-Yassky E et al. Expert Opin Biol Ther 2013;13:549-61

Antigen

Lymph node

B

TEM

Th2

Disrupted barrier

LC

DC

Initiation Acute stage Chronic stage

iDEC

DermalDC

LC

pDC

MC

EOS

MC

EOSTEM

Th22 Th22

Th17

Tc22

Th1

Th2Th2

IL-4IL-13IL-10

IL-4IL-5

TSLP

IL-22

IL-4Eotaxin-2

IL-4IL-13, No IL-10

Acanthosis

Inhibition of AMPs

Lichenification

Inmunología en DA

IL-4/IL-13

IL31

Alarminas

AMP

IL17/ IL22

Barrera

• European-American AD Th17 axis downregulated in adults withextrinsic AD

Immunopatogenesis in AD: ……more than one AD ?

• Asian AD is a disease with both psoriasis and EA-AD features, as well as robust activation of Th2, Th17, and Th22 T-cells in skin lesions

• Similar features in intrinsic AD, Asian AD and pediatric AD

Immunopatogenesis in AD: ……more than one AD ?

Vs

Inmunología en DA: leccionesdesde la psoriasis

AD vs psoriasis: brothers in arms ?

• Una gran mayoría de pacientes psoriáticos tienen enfermedad controlada al atacar el eje de células T IL-23 / Th-17 con anticuerpos dirigidos a IL-23 o IL-17

• ¿Dirigirse a un solo eje de citoquinas en la EA llevará a la supresión de la enfermedad en la mayoría de los pacientes?

• ¿ Será más adecuado el uso de estrategias “transversales”?

Puntos clave en patogénesis de DA. Implicaciones terapéuticas• Barrera epidérmica.

• Alarminas

• Prurito

• Interleucinas Th2: IL4/IL13

• Interleucinas Th1: IL-17/IL-22

• Estrategias “transversales” : JAK /Inhibidores de la fosfodiesterasa

https://doi.org/10.1016/j.ad.2019.11.002

Innovación en DA: de la patogenia a la terapéutica

Via IL4/13

Dupilumab in Th2 diseases

Adult atopic

dermatitis Asthma

AD- adolescents

AD children 6-11 years

AD children 6m-5 years

Asthma- adolescents

Asthma – 6-11 years

Nasal polyposisEosinophilic

esophagitis

Approved US FDA March 28, 2017

Ph3

Pediatric indications

Ph3

Ph2

IL-4

IL-4R c

Type I

Receptor

Type II

Receptor

IL-13

IL-4R IL-13R1

or

Management of patients with Type 2 (including Th2)-immune diseases

with high unmet medical need

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Clinical trials in Dupilumab obtained the best results in AD up to date

Is there any risk in modulation of theIL-13/IL-4 pathways ?

• Local reactions and conjunctivitis as the main adverse effects

• IL-13, IL-4 and their receptors are involved in the expulsion of parasites, the immune response to malignant cells and cardiac repair.

• A rigorous review of preclinical literature has identified only one serious safety signal for active helminth parasitic infection, and no malignancy or cardiovascular safety signals associated with modulation of the IL-13/IL-4 pathways.

▪ No clear increases in the risks of infection, malignancy or cardiovascular events noted from published clinical trials of anti-IL-13, anti-IL-4 or anti-IL-4Ra therapy

Tralokinumab is a Fully Human IL-13 Monoclonal Antibody

• Tralokinumab is a first-in-class fully human immunoglobulin (Ig)G4 monoclonal antibody with specificity for the IL-13 cytokine

• Tralokinumab potently and specifically binds to circulating IL-13 thereby preventing receptor interaction, activation, and signalling

IL-13

Tralokinumab

Brightling et al. Lancet Respir Med.2015;3:692–701; May et al. Br J Pharmacol 2012;166:177; Popovic et al. J Mol Biol 2017;429:208–219;Thom et al. PNAS 2006;103:7619; Thom et al. Methods Mol Biol 2012;805:393.

Lebrikizumab

Via IL-31

Werfel T et al. American Academy of Allergy, Asthma & Immunology 2016

Prurito y IL-31: Nemolizumab

Función barrera/AMP

• TEWL measurement at 2 months of age also was significantly predictive of AD at 12 months (P <0.05) – more than parents history of infant FLG

• Emollient use had a statistically significant protective effect, with a relativereduction in the risk of AD of 50% (relative risk, 0.50; 95% CI, 0.28-0.9; P =0.017).

Kelleher M. J Allergy Clin Immunol. 2015;135:930-935.e1.

Simpson EL,. J Allergy Clin Immunol. 2014;134:818-823.

Early use of emollient and prevention of AD

Omiganan: an AMP in topical gel for AD

• Antibiotics and antiseptics may decrease skin colonization by S. aureus but failto improve the microbiome.

• Topical treatments with corticosteroids, calcineurin inhibitors or evenmoisturizers and emollients are capable to restore barrier function and normalize skin microbiome

• Critosan/ZnO textiles could reduced S. aureus

Microbiome in atopic dermatitisClinical, Cosmetic and Investigational Dermatology, February 201710.2147/ccid.s130013

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Wiegand C, Hipler UC, Boldt S, Strehle J, Wollina U. Skin-protective effectsof a zinc oxide-functionalized textile and its relevance for atopic dermatitis. Clin Cosmet Investig Dermatol. 2013;6:115–121.

Lopes C, Soares J, Tavaria F, et al. Chitosan coated textiles may improveatopic dermatitis severity by modulating skin staphylococcal profile: a randomized controlled trial. PLoS One. 2015;10(11):e0142844.

S aureus in AD

Probiotics

• Not enough data in the literature to respond to questions regarding optimal dosing, optimal time to start treatment and duration necessary to show beneficial effects

• Most randomized controlled trials and meta-analyzes, support the administration of probiotics for at least 8 weeks with beneficial effects

Alarminas: Vía innate IDEC/ lymphoid cells-2

Mazzarana L. et al. Semin Immunopathol,2018Mazzarana L. et al. Semin Immunopathol,2018

Alarminas: Vía innate IDEC/ lymphoid cells-2

IL 33, IL25, TSLP

Thymic Stromal Lymphopoietin (TSLP)/IL33 ?

35

Yoo et al., 2005. JEM 202:541Soumelis et al., 2002. Nat Immunol 3:673Lee et al., 2010. Pediatr Allergy Immunol 21:e57

lymphoid cells-2 in AD

• Regulators of type 2 immune reactions, particularly against helminthic parasites.

• Involved in tissue homeostasis and repair

• ILC2 may contribute to increases in type 2 cytokine production in the absence of thesuppressive E-cadherin ligation

• It is likely that IL-25, IL-33, and TSLP are allinvolved in the regulation of ILC2

Mazzarana L. et al. Semin Immunopathol,2018

J. Exp. Med. 2013 Vol. 210 No. 13 2939-2950

IDEC ( inflammatory dentritic epidermic cells )

TSLP/IL33 / TSLP

Via IL23/Th17/ IL22

IL22

• IL22 desde Th22

• IL asociada a disfunción de barrera, hiperplasia epidérmica e inhibición filagrina.

• EC fase IIa, fezakinumab (ILV-094) mejoría (no significativa) frente a placebo SCORAD.

• Mayor respuesta en “inhibición del perfil genético” que clínico

• diferencias significativas en la reducción del BSA – IGA en pacientes graves.

• El beneficio en pacientes con peor respuesta al bloqueo de la vía Th2 y con mayor expresión de Th22

https://doi.org/10.1016/j.jaci.2018.07.028

Tapinarof (GSK2894512 cream) for thetreatment of atopic dermatitis

• Nonsteroidal topical agent known as therapeutic arylhydrocarbon receptor (AhR) modulating agents.

• Binding the AhR and activating the AhR pathway in multiple cells and tissue-based systems

• Controls the expression of IL-21 and IL-22 and plays an important role in the differentiation of T-helper 17 cells in vivo and in vitro

• Antioxidant by inhibiting reactive oxygen species

• Inhibition pro-inflammatory vs immunosuppressive ??

Am Acad Dermatol 2019;80:714-21.

IL-17

• Procedentes de Th17, células de inmunidad innata y células ILC

• Sobreexpresada en DA

• IL17C procedente de queratinocitos,

• Promueve diferenciación de células B Favorece síntesis de IL8, TNF, TSLP, CCL17, CSCL10

• Incrementa el defecto de la barrera epidérmica a través de filagrina

IL17A IL17 A/F IL17 CIL17B

Moléculas pequeñas en DA

https://doi.org/10.1016/j.ad.2019.11.002

AntiJAK en DA

https://doi.org/10.1016/j.ad.2019.11.002

Potential role of inhibition of intracellular signaling of multiple cytokines in AD

Company Confidential © 2018 Eli Lilly and Company

• JAK inhibition affects more than IL-4 signaling1-3

• JAK inhibition can modulate the signal of multiple cytokines important in AD:1-3

• TSLP

• IL-4

• IL-5

• IL-10

• IL-13

• IL-22

AD=atopic dermatitis; IL=interleukin; JAK=Janus kinase; Th=T helper cell; TSLP=thymic stromal lymphopoietin1. O’Shea JJ et al. Nat Rev Rheumatol 2013;9(3)173-82; 2. Zhong J et al. Database (Oxford) 2014;2014:bau007; 3. Guttman-Yassky E et al. Expert Opin Biol Ther 2013;13:549-61

Company Confidential © 2018 Eli Lilly and Company

AD=atopic dermatitis; IL=interleukin; JAK=Janus kinase; STAT=signal transducer and activator of transcription; TYK=tyrosine kinase; TSLP=thymic stromal lymphopoietin; 1. Chen L et al. Clin Exp Immunol 2004;138:375-87; 2. Guttman-Yassky E et al. Curr Opin Immunol 2017;48:68-73; 3. O'Shea JJ and Plenge R. Immunity 2012;36(4):542-50

Itch cytokines Other key AD cytokines

IL-10IL-4 IL-13IL-31 TSLP IL-22 IL-5

Baricitinib

Baricitinib modulates JAK-STAT signaling by partially inhibiting JAK1 and JAK2

IC50 nMFold selectivity vs.

JAK1

JAK1 14 1

JAK2 593 ± 118.7 42

JAK3 1860 ± 207.2 133

TYK2 2715 ± 548.7 194

Potency assessed by Ba/F3 cellular assays. IC50 = half maximal inhibitory concentration; JAK = Janus kinase; nM = nanomolar; SEM = standard error of the mean.

In vitro potency of UPA

EPO, erythropoietin; G-CSF, granulocyte colony-stimulating factor; GH, growth hormone; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; LIF, leukemia inhibitory factor; OSM, oncostatin M; PRL, prolactin; TPO, thrombopoietin; TSLP, thymic stromal lympopoietinClark JD et al. J Med Chem 2014, 57:5023-38; Huang HM et al. J Cell Biochem 2005, 96:361-75; Kouro T, Takatsu K. Int Immunol 2009, 21:1303-09; Ouyang W et al. Annu Rev Immunol 2011, 29:71-109; Zhang Q et al. Cytokine Growth Factor Rev 2008, 19:347-56

IL-22 IL-13

IL-3, IL-5, G-CSF

EPO, TPO, PRL GM-CSF, GH

IL-31, IFNγ, TSLP IL-4 IL-12, IL-23

Upadacitinib is a once-daily, oral, JAK1-selective inhibitor that targets the inflammatory pathways implicated in AD

• ASN002 is an oral dual inhibitor of Janus kinase and spleen tyrosine kinase

PAN JK/ TYK in AD

British Journal of Dermatology (2019) 181, pp733–742

JAK inhibitors in atopic dermatitis

PD4 inhibitors inm AD

1. Sawai T, et al. Br J Dermatol. 1998;138:846-848 2. Hanifin J, et al. J Invest Dermatol. 1996;107:51-56 3. Leung D, et al. J Clin Invest. 2004;113 (5):651-657 4. Jarnagin K, et al. J Drugs Dermatol. 2016;15(4):390-396

Flujo de pacientes en la Fase 3 con crisaborole: AD-301, AD-302, AD-303

23

Pomada de uso tópico con

crisaborole al 2%

Pomada de uso tópico con

crisaborole al 2%

Vehículo*

Tratamiento BID 28 días

Vehículo*

AD-301 (N = 759)NCT02118766

AD-302 (N = 763)NCT02118792

AD-303 cribado/

registro de pacientes(N = 517)

AD-301 y AD-302Estudios de eficacia y seguridad doble ciegos y controlados con

vehículos (4 semanas)

AD-303Estudio abierto de una rama a largo

plazo (48 semanas)

Fin del estudio

12 ciclos de tratamiento BID en intervalos de 28 días

ISGA≥2

ISGA≤1

En tratamiento con pomada de uso tópico con crisaborole al 2%

Fuera del tratamiento, sin fármaco del estudio

Evaluación de pacientes

Re-evaluación cada 28 días

Vehículo patentado desarrollado por Anacor.

BID=dos veces al día; ISGA=evaluación global estática del investigador.

Eichenfield et al J Am Acad Dermatol. http://dx.doi.org/101016/jaad.2017.06.010

Apremilast in AD

More PDE4 inhibitors going on in AD

Inhibidores de la vía de la sustancia P /histamina

Antagonistas del receptor de histamina 4

• Histamine, via H4R, activates mastcells, basophils, and eosinophils, and induces the production of TARC, whichreflects the clinical severity of AD.

• Also regulates the functions of notjust Th2 cells but Th1 and Th17 cells, via various receptors.

Innovación en dermatitis atópica: De la fisiopatología al tratamiento• Gran dinamismo e innovación en dermatitis

atópica

• Exploración de numerosas vías ( facilitado por la posibilidad de generar fármacos más que por fundamento patogénico firme ?)

• Vía IL4/13 y anti JAK como estrategias más prometedoras ( 2020 )

• ¿Conocemos la “diana molecular clave en DA”?

Gracias por la atención