Biologic Therapies for Atopic Dermatitis and Beyond

Transcription

1 Biologic Therapies for Atopic Dermatitis and Beyond Jonathan Corren, M.D. Departments of Medicine and Pediatrics, David Geffen School of Medicine at UCLA

2 Disclosures Genentech - research Medimmune/AZ - consultant, research Regeneron - consultant, research

3 Overview Diagnosis and natural history Pathogenesis Standard of care New treatments

4 Diagnosis and Natural History

5 Essential Features Required features: Pruritus and eczema (acute, subacute, or chronic) Typical morphology and location Chronic or relapsing history Important features (supportive) Early age of onset, personal and/or family history of IgE, IgE reactivity, xerosis Associated features Keratosis pilaris, pityriasis alba, hyperlinear palms, ichthyosis, ocular and periorbital changes

6 Typical Locations of Atopic Dermatitis Lesions

7 Classic Skin Lesions

8 Associated Skin Findings

9 Age of Onset of AD Bieber et al, J Allergy Clin Immunol, 2017!

10 Epidemiology of AD Prevalence in US %, Highest at age 4 yrs Historic data - up to 80% of children had AD remission by age 10 yr Newer data - remission occurs in only 20% > age 20 yr Prevalence similar in children, adolescents, and adults Factors associated with persistence - environmental and food allergies, other atopic diseases, lower income!

11 Proportion of AD Patients Achieving Clinical Remission

12 Age and Ethnicity-Related Differences in Cell Phenotypes and Other Markers Group! T-cell phenotype! Young! Th2, Th9, Th17 Adults! Th22 Caucasian! Filaggrin deficiency Asian! African! Th2, Th17 No flaggrin deficiency

13 Pathogenesis

14 T-cell Phenotypes in AD

15 T-cell Phenotypes in AD in Asians

16 Standard of Care

17 Joint Task Force, 2012 Versus American Academy of Dermatology, 2014

18 Topical Therapies! Therapy! AAD! JTF! Daily bath! X! X! Oatmeal or baking soda! -! X! Daily moisturizer! X! X! Barrier creams! -! X! Topical CS X! X! Preventative TCS (2x/wk)! X! X! Topical CI (>2 yr)! X! X! Preventative TCI (2x/wk)! X! X! Coal tar on scalp! -! X! Topical antihistamines! -! -!

19 Cutaneous Side Effects of Long-term TCS Use

20 Topical Therapies for Refractory Disease or Recurrent Infections Therapy! AAD! JTF! Bleach baths! X! X! Intranasal mupirocin! X! -! Topical antiseptics! -! X! Wet wraps for refractory dermatitis! X! X!

21 Phototherapy for Refractory AD Therapy! AAD! JTF! UVA for acute AD! X! X! UVB for chronic AD! X! X! Psoralen/UVA for widespread AD! Use of UV Rx for chronic AD! X! X! X! -!

22 Systemic Immune Therapies! Therapy! AAD! JTF! Cyclosporine A! X! X! Azathioprine! X! X! Methotrexate! Variable! X! Mycophenolate! Variable! X! Interferon-gamma! Variable! X! Systemic CS - acute! X! X! Systemic CS - chronic -! -! Omalizumab, IVIg, Retux! -! -! Oral antihistamines! X! X!

23 Therapies Directed at Irritants and Allergens! Therapy! AAD! JTF! Liquid detergent! -! X! Additional rinse cycle! -! X! Avoidance of occlusive clothing! -! X! Elimination diets! -! X! Allergen IT to airborne allergens! -! X!

24 Is There an Unmet Need in AD? Prevalence of severity levels: Mild >70% Moderate - 20% Severe - 2% Medications most commonly used: Topical CS % Topical CI - 23% Control of symptoms in moderate-severe - 47% Topical CI - 23%!

25 Reasons for Treatment Failure Incorrect diagnosis Lack of education and compliance with therapy Hypersensitivity reactions to topical therapy Secondary bacterial skin infections Food allergy - infants 33%, older children 5-10% Environmental allergens and irritants Psychosocial factors

26 Reasons for Poor Compliance in Atopic Dermatitis 1. Patient runs out of medication and doesn t refill it. 2. Physician unwilling to prescribe adequate amounts of medication. 3. Patient/parents unaware of correct frequency of application. 4. Application is left to children who are too young to apply 5. Perception is that treatment does not work. 6. Perception is that treatment has unacceptable side effects. 7. Perception is that treatment is cosmetically unacceptable. 8. Medication makes AD worse. 9. Medication is painful to apply.

27 New Treatments

28 Small Molecule Antagonists in Atopic Dermatitis

29 Phosphodiesterase-4 in AD PDE4 contributes to regulation of inflammatory cytokines in AD through degradation of cyclic AMP and downstream effects on factor KappaB PDE4 is increased in circulating inflammatory cells in AD Inhibition of PDE4 in monocytes in-vitro > reduced pro- inflammatory cytokines

30 PDE-4i (Crisborole) in AD Crisaborole is a low-molecular weight PDE4 inhibitor that allows for effective penetration through skin Rapidly metabolized, no systemic effects PDE4 activity Phase 1 studies conducted down to age 2 yr - no safety issues Approved by FDA for mild-moderate AD (12/2016)

31 Topical Crisaborole (PDE4i) in AD Paller et al, J Am Acad Dermatol, 2016!

32 Topical Tofacitinib (JAKi) in AD

33 Topical Tofacitinib in AD

34 Monoclonal Antibodies in Clinical Trials

35 Monoclonal Antibodies in AD Cytokine or Other Target! IgE! IL-5! IL-4R-alpha! IL-31! IL-12/IL-23p40! IL-13! TSLP! Name of MAb! Omalizumab Mepolizumab Dupilumab Nemolizumab Ustekinumab Tralokinumab Tezepelumab

36 Omalizumab in AD

37 Mepolizumab in AD Measure! Day 0! Mepo! (n=20)! Day 0! Placebo! (n=23)! Day 14! Mepo! (n=20)! Day 14! Placebo! (n=23)! Blood eos! SCORAD! TARC!

38 Dupilumab in AD (Ph2) Effects on mrna and Biomarkers

39 Dupilumab in AD (Ph2) Dose Responsiveness

40 Dupilumab in AD (Ph 3) EASI and Pruritis

41 Dupilumab in AD (Ph3) IGA and EASI-75

42 Immunologic Effects of Dupilumab

43 Nemolizumab in AD (Ph2) Dose Responsiveness

44 Summary Atopic dermatitis is the most prevalent of the chronic type-2 inflammatory diseases New topical therapies have unique effects on a number of pathways which contribute to AD across all levels of severity In more severe patients, MAb s directed against a number of cytokines, including IL-4/13, IL-31, and TSLP, appear to have robust effects with good safety profiles Potential areas of future research include long-term modulation of T memory cell and T reg cell function to achieve disease remission!