NEW AND EMERGING TREATMENTS IN BULLOUS PEMPHIGOID NEIL KORMAN, MD, - - PowerPoint PPT Presentation

NEW AND EMERGING TREATMENTS IN BULLOUS PEMPHIGOID

NEIL KORMAN, MD, PHD PROFESSOR OF DERMATOLOGY UNIVERSITY HOSPITALS CASE MEDICAL CENTER CLEVELAND, OH

NEIL J KORMAN MD, PHD 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

BULLOUS PEMPHIGOID

• Acquired subepidermal blistering disease
• Most common autoimmune blistering dis
• Primary lesion – tense blister on normal or erythematous

skin

• Often presents with urticarial plaques
• Flexural arms, legs, abdomen, groin
• Minority of pts have mucous memb disease

BULLOUS PEMPHIGOID HISTO/IMMUNOPATHOLOGY

• Histopathology – Typically shows a subepidermal blister

with an eosinophil rich inflammatory infiltrate

• DIF – Almost all have linear BM C3 and most have linear

BM IgG (some may have linear IgE)

• IIF – Circulating IgG antibodies bind epidermal side of

salt split skin

BULLOUS PEMPHIGOID ELISA

• Tests for both BP 180 and BP 230 AB
• Commercially available
• ELISA Levels of BP 180 often correlate with disease

activity

BULLOUS PEMPHIGOID COURSE AND PROGNOSIS

• Typically lasts 1-5 years
• Mortality rate vary depending upon pt country of origin
• Generally less severe than pemphigus

BULLOUS PEMPHIGOID TREATMENT

• Dictated by degree of involvement and rate of progression
• Localized disease can be treated with topical steroids
• RCT of topical vs oral steroids demonstrates both improved safety

and efficacy of topicals over orals in moderate and severe dis

• However in US majority of patients with generalized disease are

treated with systemic steroids due to practical considerations

• Many pts on oral steroids are given steroid sparing agents such as

dapsone, doxycycline and niacinamide, MTX, MMF, AZA, Rituxumab and IVIg but quality of evidence supporting use of these medications is relatively low

CORTICOSTEROID TOXICITIES

• Osteoporosis
• HPA suppression
• Myopathy
• Osteonecrosis
• Cataracts
• Hypertension
• Diabetes
• Glaucoma
• Peptic ulcer
• Psychosis
• Acne
• Skin atrophy

PLANNED OR ONGOING TRIALS OF NON-BIOLOGICS IN BP

• Two-arm, parallel group, 52-week RCT comparing the safety and

efficacy of doxycycline (200 mg daily) with oral prednisolone (0.5 mg/kg daily)

• Pts will receive fixed dose for the initial 6 weeks of treatment

(doxycycline 200 mg daily; prednisolone 0.5 mg/kg daily), after which it will be adjusted as necessary.

• 256 BP patients will be recruited in the UK and Germany.
• A noninferiority analysis of doxycycline will be compared to

prednisolone at 6 wks while safety will be assessed at 52 wks Br J Dermatol; 173:227-34, 2015

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PLANNED OR ONGOING TRIALS OF NON- BIOLOGICS IN BP

• RCT to compare efficacy and safety of topical clobetasol and

methotrexate for 4 weeks followed by methotrexate alone for 8 months with topical clobetasol alone for 9 months

• Primary endpoint will be 1 yr survival rate in both groups
• Secondary endpoints will be the initial control rate of disease,

the number of serious side effects during treatment and the number of relapses during treatment

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EMERGING NEW BIOLOGIC TREATMENTS FOR BULLOUS PEMPHIGOID

OMALIZUMAB FOR TREATMENT OF BULLOUS PEMPHIGOID

• 60 – 70% of BP pts have elevated serum IgE
• 25% of pts 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
• f asthma and chronic idiopathic urticaria

OMALIZUMAB FOR TREATMENT OF BULLOUS PEMPHIGOID

• Open label study of 6 BP pts (urticarial plaques and bullae)
• 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
• 3/6 pts responded to monotherapy
• In 2/6 pts eosinophil counts correlated w/ disease activity
• No significant toxicities were observed

JAAD 2014;71:468-74

MORE 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. Recently completed – no

results yet Rituximab: Anti CD20 mAB Targets B cell by blocking CD20 on cell surface thereby preventing development of autoantibodies directed against BP antigens

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MORE BIOLOGICS WITH POTENTIAL IN BP

AGENT MOA

IVIg Multiple different possible MOA’s QGE031: Anti IgE mAb Antibody directed against IgE. Clinical trial discontinued due to lack of efficacy TNT009 Anti-C1s antibody that selectively targets the classical complement pathway. Trial pending enrollment

EOTAXIN-1: A CHEMOKINE IMPORTANT IN EOSINOPHIL TRAFFICKING

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EOTAXIN-1 Key Regulator in: Skin

Eosinophils Mast Cells T cells Basophils Macrophages T cells

EOTAXIN-1-REGULATED CELL MIGRATION AND ACTIVATION CELLS SECRETING EOTAXIN-1

Eosinophils

BERTILIMUMAB: MAB TARGETING EOTAXIN-1

• First fully human IgG4 mAb directed against eotaxin-1
• Safe, well tolerated in primates and in single administration to

healthy volunteers: no SAE, no anti-drug antibody, high affinity and specificity for human eotaxin-1

• Selective, with rapid and lasting biological activity in Phase I

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RATIONALE FOR TARGETING EOTAXIN-1 IN BP

• Eotaxin-1 (Eo-1) is important for eosinophil transmigration
• Eo-1 is incr in serum & skin lesions of BP patients
• Eos co-localize w/basal keratinocytes w/incr Eo-1 & CCR3 expression
• CCR3 is the main receptor on eosinophils
• Eotaxin-1 is correlated with BP disease severity
• Eotaxin-1 is expressed in Th2 cells in BP lesions

Hence, Bertilimumab has the potential to eliminate the Eotaxin-1 positive feedback loop which is responsible for the recruitment of both eosinophils and Th2 cells to the site of inflammation in BP

Br J Dermatol. 2007:454-9, Br J Dermatol. 2000 112-6, Acta Derm Venereol. 2000 277-80, Immunology and Cell Biology (2000) 78, 415–422; Respiratory Research 2001, 2:150-156, Clin Exp Immunol. 2002:470-8, Eur J Dermatol. 2002;12:27-31, Am J Reprod Immunol. 2004;51:32-9, Clin Exp Immunol. 2011;166:145-53, Am J Respir Cell Mol Biol. 1999:291-5 11. J Immunol. 1999;62:2946-55

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EOTAXIN-1 LEVELS ARE INCREASED IN BP AND CORRELATE WITH DISEASE SEVERITY

Levels of Eotaxin-1 are significantly Increased both in sera and blister fluids Eotaxin-1 up-regulated in serum of BP patients and correlates with disease severity*

Eur J Derm, 12,27-31, 2002 Clin Exp Immunol. 2011;166:145-53 22

• Patients

10-15 adults newly diagnosed, moderate to extensive BP or pts on corticosteroids who cannot be successfully tapered

• Study design

Open-label, single group, 3 IV injections (Day 0, 14, 28) of bert given along with 30 mg/day oral prednisone, prednisone tapered down per protocol

• Duration

– Screening: up to 14 days – Treatment period: 28 days (3 days) – Follow-up period: 56 - 90 days (±3 days) – Total duration: 84 to 118 days (±3 days)

.

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BERTILIMUMAB BP – PHASE 2 STUDY

• Primary Objective

To evaluate the safety of bertilimumab

• Secondary Objective

To evaluate the preliminary evidence of clinical efficacy as measured by the BPDAI score (a severity

• utcome measure), proportion of patients achieving

dose of prednisone 10mg/day at Day 84)

• Pharmacokinetics and Pharmacodynamics
• Exploratory Objective

To determine change from baseline of biomarkers of inflammation

Open to enrollment in Israel and the US

BERTILIMUMAB CASE STUDY SUBJECT 02-01

• 66 year old white male, newly diagnosed with BP
• History of diabetes, diverticulosis, gastroduodenitis, anemia,

hyperlipidemia

• Concomitant medications: Lantus, sitagliptin, lansoprazole and iron

supplement

• Version 3 of the protocol, only 2 infusions bertilimumab given
• Prior treatment:

– 60 mg prednisone x 4 days, off 2 days, 40 mg 2 days, washed out for 2 weeks

• BPDAI at Day 0 = 58; BPDAI at Day 60 = 3
• Patient’s last visit day 60 at 10 mg prednisone, tapered to 5 mg day 67

SUBJECT 02-01

SUBJECT 02-01

SUBJECT 02-01 – POST STUDY FOLLOW-UP

–Treatment during the 2 following months: prednisone 5mg + 100mg minocycline – minor flares treated locally with clobetasol

• Stop
• No treatment for the next 4 months:

– single periodic bulla treated with clobetasol – investigator defined pt as in remission

• Investigator initiated randomized, placebo-controlled, phase

2, double-blind study of anti-IL-5 mAB in patients w/ BP.

• Estimated Enrollment: 30 patients
• Intervention:

– Drug: Mepolizumab (an-IL-5 antibody)

• 750mg mepolizumab four times over four months

– Drug: Placebo

• Saline placebo four times over four months
• Study recently completed – results not yet available

MEPOLIZUMAB (ANTI IL-5 AB) IN BULLOUS PEMPHIGOID

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RITUXIMAB IN BULLOUS PEMPHIGOID

• Until recently evidence for safety/efficacy of rituximab in BP

was limited to case reports and case series

• Recent study of rituximab as first line Rx in BP from Taiwan
• Retrospective study of 32 BP pts followed for one year
• 13 received 4 wkly infusions of 500 mg of ritux plus oral pred
• 19 received oral prednisolone alone
• 1 yr remission - 92% of ritux pts vs 53% of pred pts (p = .02)
• 1 yr mortality - 15% of ritux pts vs 37% of pred pts (p = .18)

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RITUXIMAB IN BP CONTINUED

• However no differences in severity of BP as measured by the BPDAI
• Also no differences in the cumulative oral steroid dose
• These results support the efficacy and safety of rituximab in BP but

conclusions are limited by small study size and retrospective design

• The results suggest the need for larger studies with longer follow-up

periods, and better design (RCT) well as the possibility of using alternate rituximab Rx regimens Brit J Derm 173:302-4, 2015.

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IVIG IN BULLOUS PEMPHIGOID

• Multicenter, RDBPCT of one course of IVIg (400 mg/kg/d x 5 d)

vs placebo in steroid resistant BP pts

• Used disease activity score (DAS) at day 15 as primary endpoint
• 56 pts enrolled (those with CV or neurologic dis were excluded

and 15 pts withdrew

• DAS score was 12.5 pts lower in the IVIg group than the placebo

group (P= 0.089) Amagai et al J Derm Sci 2017; 85:77-84

SUMMARY – WHAT’S NEW IN TREATMENT OF BP

• We look forward to the results of RCT’s of doxycycline compared to

prednisolone and MTX compared to topical corticosteroids

• The biologic revolution that has dramatically changed the landscape of

therapeutics in psoriasis is spreading to the autoimmune blistering diseases

• Omalizumab is an intriguing new approach to rx of BP
• Bertilimumab could be a new approach for rx of pts with BP
• Targeting IL-5, turning off B cell antibody production with rituximab or

treating with IVIg may also be viable approaches

• There is a strong need for more RCT’s in BP to develop better evidence for

how to safely and effectively treat this disease

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