drug development @ lied · drug development @ lied ralf ludwig lübeck institute of experimental...

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

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15

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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