1. Biomarkers: types ? Genome DNA Epigenome Genomic Biomarkers
EMA-ICH (International Conference of Harmonization) 2007/2008
DNA
Transcriptome
Genome
RNA
Epigenome
Proteomic Biomarkers
Proteome
MMP9
myomiR CK
LFTB4 ?
DISCOVERY
SPP1
VALIDATION

2. Biomarkers: clinical utility DISEASE STRATIFICATION
Diagnostic
Therapeutic
PHARMACODYNAMIC
(“what the drug does to the body”)
Confirm predicted mechanism of action
PHARMACOKINETIC
(“what the body does to the drug”)
Drug biodistribution, half-life, elimination mode
PROGNOSTIC
surrogate endpoints
THERAPIES MONITORING
Toxicity & Safety
Efficacy /responders vs non responders)
Efficiency (effective dose regimen evaluation)
DISEASE DIAGNOSIS
(GENE MUTATIONS)
DISEASE PROGRESSION
DISEASE STRATIFICATION
DISEASE SCREENING
DISEASE MECHANISMS

3. Functionally validated Biomarkers for DMD
Type
Source
Clinical mirroring
Creatine kinase (CK)
protein
serum
muscle damage (?)
Serum matrix metalloproteinase
(MMP9)
Disease progression
Dystrophin
muscle
Drug response
(pharmacodynamic biomarker)
Fibronectin
Disease severity
(age dependent)
myomiRs
RNA
Osteopontin-SSP1
SNP
DNA
Loss of ambulation
Steroid response
LFTB4

4. Novel Biomarkers for DMD Identified in patients or animal models
Type
Source
Clinical mirroring
Annexin 1
SNP
DNA
Sarcolemma repair
Titin
TTN protein
urine
Disease severity
carbonic anhydrase III
CA3 protein
Plasma/serum
Rrespiratory function
myosin light chain 3
MYL3 protein
Disease progression
malate dehydrogenase 2
MDH2 protein

5. Other Biomarkers (Imaging)
Type
Source
Clinical mirroring
STRAIN profile (LV)
cardiac magnetic resonance (CMR)
HEART
cardiomyopathy
IMAGING
MUSCLE MRI
MUSCLE
MUSCLE damage
MUSCLE MRI SPECTROSCOPY
muscle
Muscle damage

6. DYSTROPHIN IS A RELIABLE PHARMACODYNAMIC BIOMARKER
FOR DMD THERAPIES AIMING AT DYSTROPHIN RESTORATION

7. CONCLUSIONS SEVERAL VALIDATED BIOMARKERS AVAILALE FOR DMD MONITORING
DYSTROPHIN MEASURED BY QUANTITATIVE PROTEIN ANALYSIS IS A RELIABLE PHARMACODYNAMIC BIOMARKER FOR DMD THERAPIES
MEASURING DYSTROPHIN ACCURATELY AND NON-INVASIVELY COULD BE A TURNING POINT FOR CLINICAL TRIALS

8. 204th ENMC International Workshop: Title: Biomarkers in DMD
Date: 24 – 26 January 2014
Naarden (NL)
Organizers
Alessandra Ferlini
Kevin Flanigan
Francesco Muntoni
Hanns Lochmueller
Peter Bram ‘t Hoen
Elizabeth McNally

9. There are no biomarkers approved by the EMA or FDA for
REFERENCE
There are no biomarkers approved by the EMA or FDA for
clinical use in DMD

11. Biomarker clinical validation: the bottleneck
Large patients. number required
Biosamples and clinical data sharing (rare diseases)
Repetability (consolidated tools/platforms)
Detailed phenotyping
Homogenous patients cohorts
Novel statistical tools

12. future directions
Novel statistical tools to analyse small cohorts analysis which might generate controversial results
Identify novel biological source (plasma fractions, vesicles, stem cells) to biomarker search and monitoring
Exploring urine (non invasive)
Using OMIC data via novel interactome maps to biomarker discovery
Implementing searching of pharmacogenetics biomarker in clinical trials

13. Summary Many exploratory biomarkers in DMD None surrogate
Only dystrophin protein approved by FDA and EMA
Small cohorts analysis might generate controversial results
Validation needs a large number of Duchenne patients: cooperation is a must
EMA dialoguing is a must fro clinical trials
Establishing a biomarkers
Qualification is highly demanding (time/cost/effort) and requires cooperation and dialogue between industries