drug development @ lied · drug development @ lied ralf ludwig lübeck institute of experimental...
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Drug development @ LIED
Ralf Ludwig Lübeck Institute of Experimental Dermatology (LIED)
University of Lübeck, Germany
High medical need for new treatments of inflammatory skin diseases
Psoriasis • Comorbidity • Unresponsive to biologicals • High treatment cost • Mortality still increased
High medical need for new treatments of inflammatory skin diseases
Psoriasis • Comorbidity • Unresponsive to biologicals • High treatment cost • Mortality still increased
Pemphigus and Pemphigoid (AIBD) • Increasing incidence • Immunosuppression required to maintain
clinical remission • Treatment-associated adverse events • Mortality 2-3-fold increased
Pemphigus- and Pemphigoid diseases
Pemphigus (Bulous) Pemphigoid
Clin
ics
His
tolo
gy
Pemphigus- and Pemphigoid diseases
Pemphigus (Bullous) Pemphigoid
Clin
ics
Dire
ct IF
Treatment of AIBD
Pemphigus vulgaris Bullous pemphigoid
First line - High-dose systemic corticosteroids
- Combination with other immunusup..
First line - topical corticosteroids
- Combination with dapson, doxicylin
Second line / alternatives - anti-CD20 (Rituximab) - IVIG - Immunoadsorbtion / plasmapheresis - Cyclophosphamide - Combinations
Pathogenesis of AIBD
Pathways to new treatments pursued at LIED
In vitro validation
In vivo validation
Pre-clinical models
Clinical trials
Hypotheses Omics Screening Computation LIED & partners from academia and industry
Pathways to new treatments pursued at LIED
In vitro validation
In vivo validation
Pre-clinical models
Clinical trials
Hypotheses Omics Screening Computation LIED & partners from academia and industry
Use of dimethylfumarate in bullous pemphigoid (BP) and epidermolysis bullosa acquisita (EBA)
In vitro validation
In vivo validation
Pre-clinical models
Clinical trials
Hypotheses • Dimethylfumarate (DMF) established treatment of psoriasis
• DMF recently licenced for multiple sclerosis
• DMF has manifold immune-modulatory fuctions
• DMF is an effective treatment for BP / EBA
DMF impairs neutrophil activation
In vitro validation
In vivo validation
Pre-clinical models
Clinical trials
Hypotheses
Normal human serum EBA serum
DMF impairs neutrophil activation
In vitro validation
In vivo validation
Pre-clinical models
Clinical trials
Hypotheses neg pos
DMF 15 µg/ml
Use of dimethylfumarate in bullous pemphigoid (BP) and epidermolysis bullosa acquisita (EBA)
In vitro validation
In vivo validation
Pre-clinical models
Clinical trials
Hypotheses
DMF treatment improves already Established EBA
Immunization
Weeks
0 3 9
Clinical assessment Randomization to treatment
1. Solvent 2. DMF
In vitro validation
In vivo validation
Pre-clinical models
Clinical trials
Hypotheses
DMF treatment improves already Established EBA
In vitro validation
In vivo validation
Pre-clinical models
Clinical trials
Hypotheses
* * * *
Individual treatment of BP patients with DMF
In vitro validation
In vivo validation
Pre-clinical models
Clinical trials
Hypotheses
2xtgl Clobetasol* + Fumaderm®
Inclusion 4 months 16 months
Fumaderm® End of study
Endpoint: Observation
Pathways to new treatments pursued at LIED
In vitro validation
In vivo validation
Pre-clinical models
Clinical trials
Hypotheses Omics Screening Computation LIED & partners from academia and industry
High-throughput screening identifies novel neutrophil-inhibitory compounds
In vitro validation
In vivo validation
Screening
ongoing
High-throughput screening identifies novel neutrophil-inhibitory compounds
In vitro validation
In vivo validation
Screening
ongoing RO
S re
leas
e (r
el)
Inhibitory compounds #1-33 / 1.200
High-throughput screening identifies novel neutrophil-inhibitory compounds
In vitro validation
In vivo validation
Screening
ongoing
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Activatory compound Control Inhibitory compound
In vivo validation of 4 compounds
In vitro validation
In vivo validation
Screening
ongoing
DMSOMPM2
4 80 1612
5
10
0
15
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Affe
cted
bod
y s
urfa
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rea
(%)
Days
DMSO M2
Summary
1. Comprehensive drug development programm for inflammatory diseases
2. Identification of DMF as potential drug candidate for BP
3. Drug-repurposing for neutrophil-inhibitory compounds