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

Pre-Clinical studies are not predictive

Target compounds = 5000 – 6000

Pre-Clinial Studies = 250

Phase I = 5

Approved Drug = 1

Why?

• Lack of validated biomarkers• Underperforming preclinical models• Inadequate and incomplete sub-phenotyping • Insufficient understanding of disease mechanisms.

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.

Despite many challenges UBIOPRED is producing.

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

Cohorts

Adult Cohort

  Total plannedActual total

Severe Asthma 389 285Severe Asthma + smoking Hx 123 102Mild Asthma 112 113No lung disease 105 103TOTAL 729 603

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

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

Cohorts year 4 focus

• Finishing recruitment• More mild asthma bronchs• Data cleaning• Increase exacerbation visits• Publications

Multiple data types are

integrated into a

‘handprint’ to identify sub-

phentoypes.

Topographical clustering on sputum and lung function produces clear clusters.

‘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

‘Handprints’ – focus year 4

• Ongoing interim analyses• Question/publication based iterative analyses –

workflows working at full speed• Interactions with other EU/IMI projects• Publications

Laboratory Models

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

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

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

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

Human Viral Challenge models focus year 4

• Viral challenge study• Analysis plan and linkage with ‘Handprint’ teams• Storage of virus

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

Involvement of patients

• Online forum for patients initiated• Patient representative engagement in working

teleconferences• Patient representatives at yearly meeting