Michael P. Heffernan, M.DSan Luis Dermatology & Laser Clinic

Director, US Probity Medical Researchmpheffernanmd@gmail.com

DISCLOSURES

Consultant, Speaker, Investigator: Abbvie, Amgen, Brickell Biotech, Dermavant,

DS Biopharma, Eli Lilly & Co., Foamix, Incyte, Janssen, Merck/Serono, Novartis

Employee/Stockholder(ended Sept 2014): Eli Lilly & Co.

Probity Medical Research

International Consortium of Dermatology Researchers

Adding research sites all across the US

Objectives

Understand how new biologic therapies will dramatically change dermatology.

Understand how the MOA of the biologic determines which Derm diseases will be successfully treated

ARS: Which Disease has the Highest Need for a Biologic?1. Severe Atopic Dermatitis2. Hidradenitis Suppurativa3. Plaque Psoriasis4. Pemphigus Vulgaris5. Pyoderma Gangrenosa6. Chronic Urticaria

Our Current Biologics Anti-TNF

Receptor: Etanercept Antibody: Adalimumab, Infliximab, Certolizumab

Anti-IL-12/23: Ustekinumab Anti-IL-17: Secukinumab, Ixekizumab Anti-IL-17RA: Brodalumab Anti-IL-23: Guselkumab, Tildrakizumab IL-1 RA: Anakinra Anti-IL-1B: Canakinumab Anti-IgE: Omalizumab Anti-CD20: Rituximab Anti-IL-4/13: Dupilumab

Tumor Necrosis Factor(TNF)

TNF has myriad upstream and effector roles in TH1 inflammation

Receptor binds free TNF Antibodies bind free and bound TNF Both approved for PSO, PSA, RA, AS Antibodies approved for Crohns, UC and

Adalimumab is approved for HS

TNF Mediated Derm Diseases

FDA Approved: Psoriasis Hidradenitis Suppurativa

Off Label: Sarcoid GA/NLD Pyoderma Gangrenosa TEN Pityriasis Rubra Pilaris

Sarcoid

Effective: Infliximab, Adalimumab Ineffective: Etanercept, Ustekinumab,

Golimumab Drent M, Cremers JP, Jansen TL, et al.

Practical eminence and experience-based recommendations for use of TNF-alpha inhibitors in sarcoidosis. Sarcoidosis VascDiffuse Lung Dis. 2014;31(2):91–107.

Sarcoid (Cont.)

Rossman MD, Newman LS, Baughman RP, et al. A double-blind, randomized, placebo-controlled trial of infliximab in patients with active pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2006;23:201–208.

Kamphuis LS, Lam-Tse WK, Dik WA, et al. Efficacy of adalimumab in chronically active and symptomatic patients with sarcoidosis. Am J Respir Crit Care Med. 2011;184(10):1214–1216.

Sarcoid (cont.)

Judson MA, Baughman RP, Costabel U, et al. Safety and efficacy of ustekinumab or golimumab in patients with chronic sarcoidosis. Eur Respir J. 2014;44:1296–1307.

Pariser RJ, Paul J, Hirano S, et al. A double-blind, randomized, placebo-controlled trial of adalimumab in the treatment of cutaneous sarcoidosis. J Am Acad Dermatol. 2013;68(5):765–773. (10 cases/ 6 placebo)

Granuloma Annulare

Effective: Adalimumab, Infliximab Ineffective: Etanercept Min M, Lebwohl M. Treatment of

recalcitrant granuloma annulare (GA) with adalimumab: A single-center, observational study. JAAD: 74(1) 127-133 (7 cases)

Hidradenitis Suppurativa FDA Approved: Adalimumab Effective: Infliximab, Adalimumab Possible: Ustekinumab, Anakinra Ineffective: Etanercept Grant A, Gonzalez T, Montgomery MO, et al. :

Infliximab therapy for patients with moderate to severe hidradenitis suppurativa: a randomized, double-blind, placebo-controlled crossover trial. J Am Acad Dermatol. 2010;62(2):205–17.

Blok JL, Li K, Brodmerkel C, et al. : Ustekinumab in hidradenitis suppurativa: clinical results and a search for potential biomarkers in serum. Br J Dermatol.2016;174(4):839–46. (17 cases)

Pyoderma Gangrenosa

Effective: Infliximab(104), Adalimumab(15) Maybe: Ustekinumab (3), Canakinumab(6) Ineffective: Etanercept (7) The Future: anti-IL-17??? Quist, S. R. and Kraas, L. (2017),

Treatment options for pyoderma gangrenosum. JDDG: Journal der Deutschen Dermatologischen Gesellschaft, 15: 34–40.

Toxic Epidermal Necrolysis

Thalidomide trial worsened TEN Infliximab: 15 Case Reports 14/15

survive Etanercept: 12 Case Reports 11/12

survive

Pityriasis Rubra Pilaris Effective: Adalimumab, Infliximab,

Ustekinumab Petrof G, Almaani N, Archer CB, Griffiths

WAD, Smith CH. A systematic review of the literature on the treatment of pityriasis rubrapilaris type 1 with TNF-antagonists. J Eur AcadDermatol Venereol. 2013;27:e131–e135. (15 Cases)

Chowdhary M, Davila U, Cohen DJ. Ustekinumab as an alternative treatment option for chronic pityriasis rubra pilaris. Case Rep Dermatol. 2015;7(1):46-50. (4 cases, 6 since)

B Cell Derm Diseases

Pemphigus Vulgaris Pemphigus Foliaceous Paraneoplastic Pemphigus Bullous Pemphigoid Mucous Membrane Pemphigoid Epidermolyis Bullosa Acquisita Vasculitis

Anti CD20: Rituximab

CD20 is present on mature B cells. Anti-CD20 leads to sustained reduction in mature B cells

FDA approved for Lymphoma, Rheumatoid Arthritis

Rituximab for Pemphigus

Lymphoma: 375mg/m2 weekly x4 RA Protocol: 1000mg x 2 CR: 66.6%(L) vs. 75%(R) PR: 12.78%(L) vs. 23.91%(R) Relapse: 22.78%(L) vs. 35.87%(R) Ser. Infxn: 3.9%(L) vs. 15.2% (R) Mortality: 2.2% (L) vs. 1.1% (R)

Dermatol Ther (Heidelb). 2012 Dec;2(1):17

Rituximab for Pemphigus

578 patients 76% Complete Response 5.8mos mean time to remission 40% Relapse Rate 3.3% Serious Adverse Events

Acta Derm Venereol. 2015 Apr 17

Key Takeaways

We have several Biologic Medications that target specific parts of the immune system

In addition to the FDA approved indications (Psoriasis and HS), the anti-TNF antibodies (Adalimumab and Infliximab) work well for Pyoderma Gangrenosa, PRP, Granuloma Annulare and Cutaneous Sarcoid

Rituximab targets B cells and is the first line agent for pemphigus vulgaris and other AIBD’s

The Future

Biosimilars The Payor Decides Everything!!! Ask me about Probity