Transcript Kein Folientitel

Markus A. Rüegg
Biozentrum
University of Basel, Switzerland
Role of CMD Animal Models:
What is good and what are we missing?
What do we need animal experiments for?
In an ideal setting we expect answers to:
• Provide GO/NO-GO decision for sponsor to advance a new treatment
approach into clinical trials (i.e. factor of risk management)
• Generate proof of concept and in vivo efficacy data for regulatory
authorities in preparation to “first in man” studies
• Provide information on effective dose, route of administration
• Allow ranking of potential drug candidates according to efficacy (head to
head comparison; evidence for combination therapy)
• Support estimates of effect size to be expected in clinical trials
• (Generate toxicology, safety pharmacology & PK data )
What are the levels of animal experimentation?
•
academia industry
Understanding the disease: molecular level
cellular level
organ level
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Discovery of potential drug targets
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Validation of potential drug targets
•
Treatment discovery
Formal
Requirements
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Costs
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Sponsor
Each step should allow to make GO/NO-GO decisions for the
next step
Efficacy data in animalswhat is required by regulatory authorities?
Example:
EMA’s guidance document for non-clinical part of a critical assessment report:
“… mode of action and brief rationale for the development of the product in the
proposed indication should be provided”
Report on primary pharmacodynamics shall include documentation on:
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Proof of concept (in vitro and in vivo) and mode of action
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Availability of animal models relevant to the proposed indication
Unlike for toxicology studies, there are limited guidelines on the
type of efficacy studies needed to support IND filing for a new
therapeutic approach
What animal models should be used ?
Objectives:
• Provide efficacy data to support first in man study
• Increase predictability of clinical outcome based on animal data
Challenges & Bottlenecks:
• Selection of species:
rodent mammal (mouse)
non-rodent mammal (e.g. dog)
non mammal (fly, fish)
• Selection of genetic/strain background
• Selection of type of mutation:
“genotypic match”
“phenotypic match”
For genetic diseases, the genotypic match of the animal model is highly
desirable; a phenotypic match would be ideal
Issues arising using animal experiments
“Animal experiments under fire for poor design”1
Animal studies frequently poorly designed as they often are:
 Underpowered
 Unblinded
 Not randomized
“Small scale studies are pointless if they
do not produce results people have
confidence in”1
“Because animal experiments are part of the evidence used to decide which
interventions are taken forward in clinical trials, efforts to avoid bias and random
error are as important … for animal models as … for clinical trials.2
The proper conduction of animal experiments to test for efficacy is
independent of the disease investigated and is key to provide the
rationale for clinical trials
1: Jim Giles. Nature (2006), 444; 981
2: Perel et al. (2006) Br. Med. J. Dec 2006, 1-16
What is needed for effective treatment development?
• Definition of effective models for drug screening (cell models, non
mammalian systems)
• Recommendations for use of mammalian models for efficacy studies
• Consensus for disease-relevant and predictive animal model(s)
• Consensus for biochemical, histological and functional assays
• Standardization of protocols (timing of drug application,…)
• Recommendations to regulatory authorities
Specific objectives of TREAT-NMD for DMD and SMA
(kick off in 2007)
Efforts to create SOPs for
animal models of DMD
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Joint effort of several groups worldwide
Workshops held in Washington DC and Zurich
Consensus on animal models
Consensus on read-outs
Setting up of working groups to establish SOPs
SOPs published and disseminated (autumn
2008)
http://www.treatnmd.eu/research/preclinical/SOPs/
approximately 700 downloads/month
Brussels
17-19 November 2009
Efforts to create SOPs for
animal models of DMD
Evaluation of questionnaire
Brussels
17-19 November 2009
Efforts to create SOPs for
animal models of DMD
• Which readout do you routinely use?
Histology:
Molecular analysis:
Serum enzymes:
Muscle strength in vivo:
…
Imaging (MRI; Echo):
Electrophysiology:
Brussels
17-19 November 2009
100%
81%
74%
70%
20%
10%
Efforts to create SOPs for
animal models of DMD
• Satisfaction and awareness
85% know the SOPs
50% use the SOPs
> 90% would use SOPs if setting-up a new
lab
> 90% think that the SOPs help foster
faster track to treatment
Brussels
17-19 November 2009
Efforts to create SOPs for
animal models of DMD
• New issues to be addressed in DMD:
• Should there be a platform to publish
negative results?
Enthusiastically received
(> 90% thought that this is a great idea)
Brussels
17-19 November 2009
What is the situation in CMD?
Animal models:
• Heterogeneous set of diseases
• As many genetic mutations are known in humans, mice are probably the best
species to model a particular disease subtype
Subgroups:
1.
abnormalities of α-dystroglycan glycosylation and defects in other
membrane receptors (fukutin, POMGnT1, POMT1, POMT2, FKRP, LARGE,
ITGA7)
2.
abnormalities of extracellular matrix proteins (LAMA2, COL6A1, COL6A2,
COL6A3)
3.
abnormalities of nuclear proteins (Lamin A/C and nesprin)
4.
abnormalities at the level of the endoplasmic reticulum (SEPN1).
Additional mouse models need to be developed
What is the situation in CMD?
Experimental protocols:
• Many protocols developed for DMD can be adapted for CMD
• Development of a site where these protocols can be deposited and updated
(TREAT-NMD?)
There is a clear need for a person who coordinates and “pushes” such
project forward