New  and  Emerging  Treatments  in  Pemphigus  and  Bullous  Pemphigoid

Neil Korman, MD, PhD University Hospitals Case Medical Center

Cleveland, OH

Conflicts of Interest

•  Director of Clinical Trials Unit at UHCMC - many conflicts - none relevant to this talk

•  Consultant and Chair, Scientific Advisory Board, - Immune Pharmaceuticals

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 Neil  J  Korman  MD,  PhD  

Current  Treatments  for  Bullous  Pemphigoid •  Topical and Oral Corticosteroids •  Oral Anti-inflammatory Therapies – Tetracycline

Antibiotics, Niacinamide, Dapsone •  Oral Immunosuppressive Therapies – Cellcept,

Imuran, Methotrexate •  Intravenous Therapies – Rituximab, Intravenous

Immunoglobulins

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Emerging  Treatments  in    Bullous  Pemphigoid

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Omalizumab  for  Treatment  of  Bullous  Pemphigoid

•  60  –  70%  of  BP  pts  have  elevated  serum  IgE •  25%  of  patientss  have  linear  deposits  of  IgE  at  the  

epidermal  BM  on  DIF •  Omalizumab  is  a  humanized  monoclonal  AB  that  blocks  

binding  of  IgE  to  its  receptors   •  Omalizumab  is  FDA  approved  for  treatment  of  asthma  

and  chronic  idiopathic  urticaria

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Omalizumab  for  Treatment  of  Bullous  Pemphigoid

JAAD  2014;71:468-­‐‑74  

•  6  typical  (urticarial  plaques  and  bullae)  BP  pts •  All  had  either  elevated  IgE  or  eosinophil  counts •  All  had  steroid  refractory  disease  and  were  dosed  at  300  

–  400  mg  q  2  –  6  wks •  5/6  pts  responded  to  omalizumab  with  no  AE’s •  3/6  pts  responded  to  monotherapy   •  In  2/6  pts  eosinophil  counts  correlated  w/  disease  activity

AGENT MOA

Bertilimumab: Anti Eotaxin-1 mAb

Prevents Eotaxin-1-induced chemotaxis of eosinophils and neutralizes Eotaxin-1 in the circulation, preventing eosinophil migration

Mepolizumab: Anti IL-5 mAb Prevents IL-5 mediated release of eosinophils from bone marrow into blood

Complement Inhibitors Inhibits the deposition and activation of complement pathway

QGE031: Anti IgE mAb Antibody directed against IgE. Clinical trial discontinued due to side effects

New  Biologics  With  Potential  in  BP

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Eosinophil  Predominance  in  BP  Inflammatory  Process:    Role  for  Eotaxin-­‐‑1

Eotaxin-1 levels are increased both in sera and blister fluids

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Eotaxin-1 is up-regulated in BP serum and correlates w/ disseverity*

Eotaxin-­‐‑1  Levels  in  Bullous  Pemphigoid

† PV - pemphigus vulgaris

Eur  J  Derm  12:27-­‐‑31,  2002 Clin  Exp  Immunol  166:145-­‐‑53,  2011

An  Open-­‐‑Label,  Proof  of  Concept  Study  Designed  to  Evaluate  the  Safety,  Efficacy  and  

Pharmacodynamic  Effect  of  Bertilimumab  in  Patients  with  Newly  Diagnosed,  Moderate  to  

Extensive  Bullous  Pemphigoid

Study  Product: Bertilimumab

Indication: Newly  Diagnosed,  Moderate  to  Extensive  Bullous  Pemphigoid

Protocol  Number Immune/BRT/BP-­‐‑01

Phase: 2a

Principal  Investigator:

Prof  Eli  Sprecher,  MD, Professor  of  Dermatology, Sackler  Medical  School, Tel  Aviv  University, Tel  Aviv,  Israel

•  Patients: 15 adults with newly diagnosed, moderate to severe Bullous Pemphigoid

•  Primary Objective: o  To evaluate the safety and

efficacy of bertilimumab in patients with newly diagnosed, moderate to severe BP.

•  Secondary Objective: o  To evaluate additional

efficacy measures and pharmacodynamic effect of bertilimumab

•  Study design Open-label, single group

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Phase  2  Bertilimumab  (Anti  Eotaxin-­‐‑1  mAb)  Study

Additional studies as well as US IND are pending

•  Randomized, placebo-controlled, phase 2, double-blind study of anti-IL-5 mAB in patients w/ BP

•  Estimated enrollment: 30 patients •  Intervention:

o  Drug: mepolizumab (an-IL-5 antibody) •  750mg mepolizumab four times over four months

o Drug: Placebo •  Saline placebo four times over four months

•  Currently recruiting in Berne, Switzerland

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Mepolizumab  in  Bullous  Pemphigoid

•  Oral corticosteroids •  Oral anti-inflammatory therapies – Dapsone,

sulfasalazine and pentoxifylline •  Oral immunosuppressive therapies – Cellcept,

Imuran, Cytoxan, methotrexate •  Intravenous therapies – Rituximab, intravenous

immunoglobulins, Cytoxan, corticosteroids, plasmapheresis

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Current  Treatments  for  Pemphigus

Emerging  Treatments  and  Clinical  Trials    in  Pemphigus

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•  Randomized, controlled, non-blinded 6 month trial of 46 PV patients given either prednisolone and azathioprine (2.5 mg/kg) or prednisolone and tacrolimus (0.05 mg/kg)

•  All patients had same steroid taper over 10 weeks •  Time to cease blistering and disease remission were

same for Tacro and azathioprine Rxd patients •  Slightly more side effects in azathioprine group

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Pemphigus  Vulgaris  Treatment  With  Oral  Tacrolimus

J  Derm  Treat  26:  90-­‐‑3,  2015

AGENT MOA VAY  736:  Anti  BAFF  mAb Prevents  activation  of  B  cell  

activating  factor,  cell  surface  receptor  on  B  lymphocytes

Ofatumumab:  CD20  mAB mAB  that  binds  to  CD20,  cell  surface  receptor  on  B  lymphocytes

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New  Biologics  in  Pemphigus

•  VAY - 736 •  Antibody to BAFF – B cell activating factor, a cell

surface receptor on B lymphocytes •  Phase 2, placebo controlled study •  Pts with mild – moderate PV •  Intravenous infusion of VAY - 736 compared to

placebo – enrolling in the US and other countries •  No results currently available

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Emerging  Clinical  Trials  in  Pemphigus  

•  Randomized, double-blind, placebo-controlled, study of ofatumumab in pemphigus vulgaris

•  Ofatumumab is a human mAB directed against CD20 - dosed subcutaneously

•  Phase 3 multicenter trial, half of patients will get placebo for the full 56 week study period

•  Patients must previously been on prednisone > 20 mg daily and must have previously failed a steroid taper

•  Primary endpoint is time to sustained remission on minimal dose oral corticosteroids

•  Enrolling in US & other countries – no data yet

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Emerging  Clinical  Trials  in  Pemphigus  

•  Randomized study of Rituximab vs MMF in Pemphigus Vulgaris

•  Phase 3 Double blind study •  Patients will receive either Rituximab and MMF

placebo or Rituximab placebo plus MMF •  Patients must have mod-severe PV •  Patients must be on 60 – 120 mg of prednisone •  Enrollment in this trial has not begun

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Emerging  Clinical  Trials  in  Pemphigus