New and Emerging Treatments in Pemphigus and Bullous

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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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
•  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
JAAD 2014;71:468-­‐‑74 6
New Biologics With Potential in BP
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
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Eosinophil Predominance in BP Inflammatory Process: Role for Eotaxin-­‐‑1
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Eotaxin-­‐‑1 Levels in Bullous Pemphigoid
Eotaxin-1 levels are increased
both in sera and blister fluids
†
Eotaxin-1 is up-regulated in BP
serum and correlates w/
disseverity*
PV - pemphigus vulgaris
Eur J Derm 12:27-­‐‑31, 2002
Clin Exp Immunol 166:145-­‐‑53, 2011
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Phase 2 Bertilimumab (Anti Eotaxin-­‐‑1 mAb) Study
•  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
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
Additional studies as well as US IND are pending
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Mepolizumab in Bullous Pemphigoid
•  Randomized, placebo-controlled, phase 2, doubleblind 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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Current Treatments for Pemphigus
•  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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Emerging Treatments and Clinical Trials in Pemphigus
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Pemphigus Vulgaris Treatment With Oral Tacrolimus
•  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
J Derm Treat 26: 90-­‐‑3, 2015
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New Biologics in Pemphigus
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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Emerging Clinical Trials 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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