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HOMAGE Report Summary

Project ID: 305507
Funded under: FP7-HEALTH
Country: France

Periodic Report Summary 4 - HOMAGE (Heart OMics in AGEing)

Project Context and Objectives:
Despite major progress in heart failure (HF) with reduced ejection fraction (HFREF), HF mortality is still alarmingly high. No progress has been made in HF with preserved ejection fraction (HFPEF) and in acute HF. HOMAGE calls for a disruptive strategic approach, combining knowledge based on i) underlying mechanisms, ii) omics bioprofiling, iii) and co-morbidities.
In summary, the objectives of the HOMAGE consortium are:
• Objective 1: Help the identification of patients at risk of developing HF before the onset of the symptoms
• Objective 2: Help the identification of sub-sets of patients who are more likely to respond to specifically targeted therapies (personalized medicine)
• Objective 3: Assess the predictive value of biomarker for other co-morbidities commonly associated to HF and ageing.
HOMAGE will identify the most promising ‘omics-based’ BM profiles for the pre-symptomatic diagnosis and future prediction of HF in patients at risk. The predictive value of the BMs for other co-morbidities commonly associated with HF and ageing will also be investigated.
Furthermore, in a prospective trial, we will investigate the potential for targeting preventive therapy at patients with the greatest likelihood of response and the lowest risk of adverse effects. The HOMAGE consortium is to deliver a randomized controlled trial delivering a mineralocorticoid antagonist (MRA) to older people who have cardiovascular disease and evidence of cardiac dysfunction who are at increased risk of developing HF. The trial will investigate whether the MRA can reduce markers of myocardial fibrosis and whether bio-markers can prospectively identify responder-patients with a favorable benefit/risk profile.
This proof-of-concept study will help design large future biomarker-guided, personalised medicine, outcome studies leading to treatments aiming at delaying or preventing the onset of heart failure. The information gained may also be applied to many other therapeutic areas, especially where prevention of disease is the target.
Our selection of innovative ‘omics-based BMs is based on knowledge of biological pathways of the disease, which may facilitate identification of ‘Biotargets’ for future therapies. On the economic side, HOMAGE will act as an economic catalyst for European SMEs in the field of cardiovascular and ageing BMs, estimated to peak annual turnovers of up to 800 M€.

Project Results:
Merged clinical database: HOMAGE has assembled a large clinical database, currently totaling 46 134 subjects, from 21 studies in 8 European countries and 1 US study, representative of a variety of demographic characteristics. The database includes heart failure patients, patients at cardiovascular-risk and healthy subjects with up to 10 years follow-up. We conducted a subject-level meta-analysis to identify risk factors and to develop a risk prediction model for incident HF. Time-to-event analysis was conducted by using Cox proportional hazard models stratified by study. In the population sub-cohorts, during a follow-up of 6.2 years, 589 of 4438 participants (mean age 73.4±3.8 years, 51% women) developed HF. In the patient sub-cohorts, 25059 patients at risk for cardiovascular disease were included (mean age 65.9±9.2 years, 30% women) of which 526 developed HF. Sex (male), higher age, body mass index, systolic and lower diastolic blood pressure (only in the population cohort), and heart rate, lower estimated glomerular filtration rate (eGFR), smoking, history of cardiovascular disease, diabetes mellitus and use of antihypertensive medication were significant predictors of HF. We developed HOMAGE HF risk scores and showed that incident HF risk can be reliably estimated in both general and in patient populations. The risk scores may aid in risk stratification and future HF prevention strategies. These will be used as the benchmark against which novel predictive omics biomarkers will have to be validated.
The HOMAGE clinical database is linked to a centralized biobank in Maastricht (UM) (ISO9001-certified). The UM biobank has collected over 8.000 biosamples from HOMAGE partners. All these biosamples associated data to the clinical-associated data.
HOMAGE consortium agreed on consensual HF definitions which are used for validating retrospectively the ability of candidate BMs to predict the development of HF in older people. Using two HF definitions (HF defined by reported hospitalization for HF and defined by echocardiographic parameters) HOMAGE consortium has selected the first set of cases and controls for a total of 2,817 individuals (“new onset” HF cases and controls).
Several bioassay platforms have been already validated. The Proseek (Olink) proteomic plateform has been validated and was selected against other commercially available platforms. Metabolomic, miRNA, transcriptomic and urinary peptidomic methodologies have been established.
In a first derivation phase, approx. 50 proteomics biomarkers were found to be highly associated with new onset HF and 12 were found to be strongly associated with diastolic dysfunction in independent cohorts (P value< 0,0001). Although both studies are using different endpoints, 5 biomarkers are strongly associated with HF in both studies.
We investigated the association between 1H-NMR spectroscopy derived metabolite and lipoprotein measures and incident HF and found a limited number of metabolomic biomarkers improving prediction over the clinical score. Other miR markers and Collagne biomarkers are being investigated and a replication phase is planned, within HOMAGE samples We are also partnering with a number of other international groups with biomarker programs, such as the Framingham Heart Study and the ARIC study, both from the USA (Boston), and a team from Barcelona with the aim of external replication of HOMAGE findings, and the HERMES (HF molecular epidemiology for therapeutic targets) from UK in order to explore which among our predictive biomarkers cross with genetic SNPs also predictive of HF.

Recruitment in the proof-of-concept trial investigating whether the MRA can reduce markers of myocardial fibrosis and whether bio-markers can prospectively identify responder-patients with a favorable benefit/risk profile is ongoing . By 31th January 2017 (Month 48), a total of 238 patients had been consented and 146 patients had been randomized in the HOMAGE study

Potential Impact:
HOMAGE will:
- Increase the number of healthy life years by using a novel biomarker (personalized) approach to prevent and/or institute earlier treatment of HF, an extremely common disease of the elderly;
- Help to reduce costs and relieve the burden on the healthcare system by targeting diagnosis and treatment of heart failure, a common and costly disease;
- Encourage research and innovation efforts and increase business opportunities among the associated SME partners MOS, ASC, who are amongst the most experienced SMEs in the field;
- Address the impending global HF epidemic, especially in threshold countries such as China, India, Brazil, and Russia, who have rapidly growing ageing populations.

With regard to the specific Call HOMAGE will:
o Retrospectively validate Omics-based biomarkers of known, but preliminary, value in HF (Galectin-3, a marker of fibrosis; microRNAs; proteomic and metabolomic markers) in large integrated HOMAGE cohort including over 45,000 patients derived from internationally recognized to be major studies. The focus will be on assessing the value of these biomarkers for making the early diagnosis of HF in high risk elderly people, and for identifying elderly patients who may benefit from early treatment;
o Prospectively study a cohort of 800 people at risk for HF, who will be stratified to treatment with the mineralocorticoid receptor antagonist spironolactone according to their level of Galectin-3. The hypothesis is that the level of Galectin-3 predicts antifibrotic treatment efficacy as assessed by the marker Pro- Collagen III N-terminal peptide (PIIINP) and clinical outcomes;
o Benefit patients in terms of personalizing/tailoring HF treatment with the goal of avoiding unnecessary (or ineffective) treatment and side effects, thereby improving cost-effectiveness;
o Support the competitiveness of three leading European SMEs in the field through:
a. Providing unprecedented access to amongst the largest patient cohorts in the world;
b. Fostering their interaction with leading clinicians in the field and between the SMEs;
c. Engaging the power of leading experts in biomedical statistics and bioinformatics;
d. Providing seed funds to progress clinical assay development which will greatly facilitate their visibility to investors who are needed to inject sufficient funds to bring the assays to the market.
HOMAGE will serve as a conduit to the global heart failure biomarker market which is estimated to amount to between €50-800 million peak annual revenue.

List of Websites:


Marie-Ange LUC, (Déléguée Régionale Grand Est)
Tel.: +33 3 88 10 86 56
Fax: +33 3 88 10 8175
Record Number: 199602 / Last updated on: 2017-06-21
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