u-biopred (unbiased biomarkers in prediction of respiratory disease outcomes) → a 5-year european...
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U-BIOPRED (Unbiased BIOmarkers in PREDiction of respiratory disease outcomes)
→ a 5-year European project to understand more about severe asthma
Update: start of project year 4
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Pre-Clinical studies are not predictive
Target compounds = 5000 – 6000
Pre-Clinial Studies = 250
Phase I = 5
Approved Drug = 1
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Why?
• Lack of validated biomarkers• Underperforming preclinical models• Inadequate and incomplete sub-phenotyping • Insufficient understanding of disease mechanisms.
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Hypothesis
The use of biomarker profiles comprised of various types of high-dimensional data, integrated with an innovative systems biology approach into distinct phenotype handprints, will enable significantly better prediction of therapeutic efficacy than single or even clustered biomarkers of one data type, and will identify novel targets.
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Despite many challenges UBIOPRED is producing.
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What UBIOPRED is producing:
Large cohort & biobank of deeply phenotyped adult and paediatric patients
‘Handprints’: stratification of severe asthma
Preclinical models more reflective of clinical disease
A GMP viral challenge exacerbation model
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Cohorts
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Adult Cohort
Total plannedActual total
Severe Asthma 389 285Severe Asthma + smoking Hx 123 102Mild Asthma 112 113No lung disease 105 103TOTAL 729 603
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Paediatric Cohort
Total plannedActual total
School aged severe asthma 115 102School aged mild asthma 50 56Pre-school severe wheeze 73 54Pre-school mild/mod wheeze 60 46TOTAL 298 258
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Cohorts year 3
Achievements
• Recruitment accelerated• Interim analysis
conducted
Challenges
• Data cleaning– More resource to be
applied
• More mild asthma bronchs needed– Recall subjects for bronchs
• # of exacerbation visits– More focus
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Cohorts year 4 focus
• Finishing recruitment• More mild asthma bronchs• Data cleaning• Increase exacerbation visits• Publications
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Multiple data types are
integrated into a
‘handprint’ to identify sub-
phentoypes.
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Topographical clustering on sputum and lung function produces clear clusters.
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‘Handprints’ year 3
Achievements• Analysis workflows established
and tested• transMART knowledge
management platform in use– Now supported by eTRIKS
• Interim analysis shows clustering with lipidomics
• Preliminary ‘Handprints’ (clusters)
Challenges• Waiting for samples and clean
data– Interim analyses done on
what is available• Coordinating analysis efforts
– Meetings every 2 months
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‘Handprints’ – focus year 4
• Ongoing interim analyses• Question/publication based iterative analyses –
workflows working at full speed• Interactions with other EU/IMI projects• Publications
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Laboratory Models
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Step 1: establish “asthmatic phenotype”
AHR induction by passive sensitization ?
Pre-incubation with serum of
non-allergic donor
Pre-incubation with serum of
allergic donor
Images before allergen exposure Images after allergen exposure
Precision lungs are a promising model
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Laboratory models year 3
Achievements• Determined that chronic House
Dust Mite mouse model cannot be exacerbated by virus
• Establihsed CFA/HDM model in two company and one academic institution
– Has mixed Th1/Th2/Th17 phenotype and can be exacerbated.
• Explant model established• Promising work on precision cut
lung slices
Challenges• Getting viral exacerbations
– Switch to influenza from rhinovirus
• Linking with clinical data– Lipidomics to be done in
light of interim analysis results
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Laboratory models focus year 4
• 5 publications early 2013• Transcriptomics and analyte panels on samples• Getting data into transMART• Establish CFA/HDM in other labs• Development of precision cut lung models
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Human Viral challenge model year 3
Achievements• GMP virus produced• Protocol for viral challenge
study developed• Study team organized
Challenges• Viral production low titre
– Rerun at subcontractors cost – now with good titre
• Virus with reverse transcriptase activity– Proven non-infective and is
a known artifact• Withdrawal of Pfizer
– Roche temporarly then left– Now with Merck and Merck
study team
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Human Viral Challenge models focus year 4
• Viral challenge study• Analysis plan and linkage with ‘Handprint’ teams• Storage of virus
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UBIOPRED Collaboration
Successes• Two new partners• Exactly the same animal model
established in 3 different laboratories
• Linkage with eTRIKS – IMI’s translational research knowledge management project
• Every working group contains crucial members from both EFPIA and Academic partners
Challenges• Withdrawal of Pfizer• Re-organization to enable
focus on analysis• Shifting resource
committments• Delays in contracting & direct
financial distribution
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Involvement of patients
• Online forum for patients initiated• Patient representative engagement in working
teleconferences• Patient representatives at yearly meeting
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