IRDiRC: State of the Art

Paul Lasko, PhD

Canadian Institutes of Health Research

Chair, IRDiRC Executive Committee

1

Rare disease research in 2010

Large-scale global effort but there is substantial fragmentation.

Huge variations among different countries as to availability of diagnostics and therapeutics.

Breakthrough in genomic sequencing technology that greatly lowers cost and makes feasible diagnostic exome sequencing.

Improved international collaboration and coordination could better facilitate research and could reduce inequities

for patients.

International Rare Disease Research Consortium (IRDiRC)

Cooperation at international level

to stimulate, better coordinate and maximize output of rare disease

research efforts around the world

4

IRDiRC – basic principles

Co-operation at international level to stimulate, better coordinate & maximise output of rare disease research efforts around the world

Teams up public and private organisations investing in rare diseases research

Research funders with relevant programmes >$10 million US over a 5-year period can join & work together

Each organisation funds research its own way

Funded projects adhere to a common framework

5

Goals of IRDiRC by 2020

200 new therapies for rare diseases

Means to diagnose most rare diseases

6

Current status of researchin the field of rare diseases

based on Orphanet data

7

5707 ongoing research projects, covering 2129 diseases, excluding clinical trials

European rare diseases research landscape (36 countries)

(February 2014)

513 Gene search

595 Mutations search

281 Gene expression profile

393 Genotype-phenotype correlation

1048 In vitro functional study

509 Animal model creation / study

748 Human physiopathology study

179 Pre-clinical gene therapy

90 Pre-clinical cell therapy

31 Pre-clinical vaccine development

452 Observational clinical study

224 Epidemiological study

295Diagnostic tool / protocol

development

158 Biomarker development

25Medical device / instrumentation

development

79 Health sociology study

15 Health economics study

72Public health / health services

study

8

Possibility to diagnose Rare Diseases:over 2 362 genes tested to date

Number of genes tested by country Number of rare diseases tested by country

(April 2014)9

Number of genes tested in eachcountry in Europe by year

2010 2011

20122013

Medicinal products on the European market in 2013

67 orphan medicinal products

92 medicinal products without orphan designation with at least an indication for a rare disease or a group of rare disease

(January 2014)

Percentage of clinical trials by category

International rare diseases clinical trial landscape

2476 ongoing national or international clinical trials for 629 diseases in 29 countries

(April 2014) 12

1%

78%

1%

2%

16%1% 1% cell therapy clinical trial

drug clinical trial

gene therapy clinical trial

medical device clinical trial

protocol clinical trial

vaccine clinical trial

other trial

IRDiRC—ambitious goals (diagnostic tools for

all rare diseases, 200 new therapies by 2020)

Growth of IRDiRC

Third coordination meeting was held in Montreal (9-10 Oct 2011), sponsored by IG and Genome Canada.

Initially involved EU, NIH, Canada, Italy, Spain.

Funder members commit a minimum of USD 10M to rare disease research over a 5-yr period.

Present commitment exceeds $1B worldwide.

Formally launched in 2012, first public symposium held in Dublin in April 2013.

Second public symposium planned for Shenzhen, China, November 7-9, 2014.

Instruments to reach the goals

Increase research volume

Boost cooperation between researchers

Speed up R&D

15

While the pace of gene discovery based on whole exome sequencing is increasing…

…it will need to triple for IRDiRC’s 2020 goal to be met!Boycott et al. (2013)Nature Reviews of Genetics

Boycott et al. (2013)Nature Reviews of Genetics

(EMA approvals)

The rate of approvals for new orphan therapeutics is not yet increasing

Boycott et al. (2013)Nature Reviews of Genetics

Many different technologies show promise for orphan disease treatment

Principles applying to research activities

19

Sharing and collaborative work in RD research

Sharing of data and resources

Rapid release of data

Interoperability and harmonization of data

Data in open access databases

Scientific standards, requirements and regulations in RD research

Projects should adhere to IRDiRC standards

Develop ontologies and biomarkers

Cite use of databases and biobanks in publications

Principles applying to research activities

20

Participation by patients and / or their representatives in research

Act in the best interest of patients

Involve patients in all aspects of research

Involve patients in governance of registries

Involve patients in the design, conduct and analysis of clinical trials

Acknowledge patients’ contribution in articles

Principles applying to Funding Bodies

21

Promote the discovery of genes

Promote the development of therapies

Fund pre-clinical studies for proof of concept

Promote harmonization, interoperability, sharing, open access to data

Promote coordination between human and animal models

Promote active exchanges between stakeholders through dissemination of ongoing projects and events

Indicators of output

22

Research activity

No. of IRDiRC members / allocated budget

For diagnostics

No. of new causative genes discovered / No. of clinicaltests of diagnostics/ No. of diseases with available test / by country and by region

For therapeutics

No. of designations / No. of clinical trials / Attrition rate / No. of diseases covered/ Type of products

No. of disease registries / sources of clinical data

• Australia– Western Australian Department of Health

• Canada– Canadian Institutes for Health Research– Genome Canada

• China– Beijing Genomics Institute– Chinese Rare Disease Research Consortium

• EU– European Commission

• Finland– Academy of Finland

• France– French Association against Myopathies– Agence National de la Recherche– Lysogene

• Georgia– Children’s New Hospital Management Group

• Germany– Federal Ministry of Education and Research

• Italy– Italian Higher Institute of Health– Telethon Foundation

• International Consortium– E-RARE 2 Consortium

• Netherlands– The Netherlands Organization for Health Research

and Development– Prosensa

• Republic of Korea– Korean National Institute of Health

• Spain– National Institute of Health Carlos III

• UK– National Institute for Health Research

• USA– Food and Drug Administration Orphan Products

Grants Program– Isis Therapeutics– National Human Genome Research Institute (NIH)– National Center for Advancing Translational

Sciences (NIH)– National Cancer Institute (NIH)– National Eye Institute (NIH)– National Institute of Neurological Disorders and

Stroke (NIH)– National Institute of Arthritis and Musculoskeletal

and Skin Diseases (NIH)– National Institute of Child Health and Human

Development (NIH)– NKT Therapeutics– Office of Rare Diseases (NIH)– PTC Therapeutics– Sanford Research Institute

• International Pharma Companies– Genzyme (Sanofi)– Shire

Present list of IRDiRC funder members

New members wanted

Members can be public or private sector entities, profit or non-profit organizations.

Members must pledge a minimum of USD 10 million for rare disease research over the next five years. This money is not given to IRDiRC but is spent on internal programs.

Members must agree to follow IRDiRC policies and guidelines (available on www.irdirc.org).

Every member has one seat on the Executive Committee and can nominate one member to one Scientific Committee or Working Group.

Governance structure

2525

Executive Committee: FUNDING AGENCIES

26

Paul Lasko (chair of IRDiRC)

•Canadian Institutes for Health Research

•Canada

Christopher Austin

•National Center for Advancing Translational Sciences (NIH)

•USA

Pedro Cortegoso Fernández

•National Institute of Health Carlos III

•Spain

Hugh Dawkins

•Western Australian Department of Health

•Australia

Ruxandra Draghia-Akli

•European Commission

•Europe

Stephen Katz

•National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH)

•USA

Enrico Garaci

•Istituto Superiore de Sanita

•Italy

Nicolas Lévy

•French Foundation for Rare Diseases

•France

Pamela McInnes

•Office of Rare Diseases (NIH)

•USA

Pierre Meulien

•Genome Canada

•Canada

Lucia Monaco

•Telethon Foundation

•Italy

Katherine Needleman

•Office of Orphan Products Development (FDA)

•USA

Executive Committee: FUNDING AGENCIES

27

Marie-Christine Ouillade

•French Muscular Dystrophy Association

•France

Willem Ouwehand

•National Institute for Health Research

•UK

Melissa Parisi

•National Institute of Child Health and Human Development (NIH)

•USA

Hyun-Young Park

•Korea National Institute of Health

•Korea

Jeffery Schloss

•National Human Genome Research Institute (NIH)

•USA

Ralph Schuster

•Federal Ministry of Education and Research

•Germany

Bertrand Schwartz

•Agence Nationale de la Recherche

•France

Danilo Tagle

•National Institute of Neurological Disorders and Stroke (NIH)

•USA

Edward Trimble

•National Cancer Institute (NIH)

•USA

Santa Tumminia

•National Eye Institute (NIH)

•USA

Sonja van Weely

•The Netherlands Organisation for Health Research and Development

•Netherlands

Heikki Vilen

•Academy of Finland

•Finland

Executive Committee

28

INDUSTRYKaren Aiach

•Lysogene

•France

Luc Dochez

•Prosensa

•Netherlands

Diane Goetz

•PTC Therapeutics

•USA

Carlo Incerti

•Genzyme

•USA

Robert Mashal

•NKT Therapeutics

•USA

Brett Monia

•Isis Pharmaceuticals

•USA

Philip Vickers

•Shire

•USA

Béatrice de Montleau

•European Organisation for Rare Diseases (EURORDIS)

•Europe

Peter Saltonstall

•National Organization for Rare Disorders (NORD)

•USA

Sharon Terry

•Genetic Alliance

•USA

PATIENT ORGANISATIONS

Executive Committee

29

Ning Li

•Beijing Genomics Institute (BGI)

•China

David Pearce

•Sanford Research

•USA

Qing K Wang

• Chinese Rare Disease Consortium

• China

Oleg Kvlividze

•Children’s New Hospitals Management Group

•Georgia

Daria Julkowska

•E-RARE 2 Consortium

•Europe

RESEARCH INSTITUTES

CONSORTIUM OF RESEARCH INSTITUTES

HOSPITALS

CONSORTIUM OF FUNDING BODIES

Diagnostics Scientific Committee (DSC)

30

Kym Boycott (chair)

•Children's Hospital Eastern Ontario

•Canada

Han Brunner

•Nijmegen University Hospital

•Netherlands

Michael Bamshad

•Seattle Children's Hospital

•USA

Johan Den Dunnen

•Center for Human and Clinical Genetics

•Netherlands

Xavier Estivill

•Genomic Regulation Centre

•Spain

Milan Macek

•Charles University Prague

•Czech Republic

Gert Matthijs

•University Hospital Leuven

•Belgium

Woong-Yang Park

•Samsung Genome Institute

•Korea

Peter Propping

•University of Bonn

•Germany

Pak-Chung Sham

•Chinese Rare Disease Research Consortium

•China

Jun Wang

•BGI

•China

Interdisciplinary Scientific Committee (ISC)

31

Hanns Lochmüller (chair)

•University Newcastle upon Tyne

•UK

Jamel Chelly

•National Institute of Health and Medical Research

•France

Angel Carracedo

•University of Santiago de Compostela

•Spain

Jack Goldblatt

•Genetic Services and the Familial Cancer Program of Western Australia

Petra Kaufmann

•National Institute of Neurological Disorders and Stroke

•USA

Alastair Kent

•Genetic Alliance

•UK

Jeffrey Krischer

•University of South Florida

•USA

Bartha Maria Knoppers

•McGill University

•Canada

Samantha Parker

•Orphan Europe Recordati Group

•France

Rumen Stefanov

•Medical University of Plovdiv

•Bulgaria

Domenica Taruscio

•Italian National Centre for Rare Diseases

•Italy

Therapies Scientific Committee (TSC)

Yann Le Cam (chair)

•EURORDIS (France)

Gert-Jan Van Ommen

•Leiden University Medical Centre (Netherlands)

Giles Campion

•Prosensa Therapeutics (Netherlands)

Seng Cheng

•Rare Diseases Science Genzyme Corporation (USA)

Adam Heathfield

•Pfizer (UK)

Maria Mavris

•EURORDIS (France)

Fulvio Mavilio

•Genethon (France)

John McKew

•NIH (USA)

Elizabeth McNeil

•NIH (USA)

Luigi Naldini

•Telethon Institute (Italy)

Glen Nuckolls

•NIH (USA)

Asla Pitkänen

•University of Eastern Finland (Finland)

Karin Rademaker

•University Medical Centre (Netherlands)

Robert Schaub

•NKT Therapeutics (USA)

Josep Torrent i Farnell

•Spanish Medicines Agency (Spain)

Marc Walton

• FDA (USA)

Ellen Welsh

•PTC Therapeutics (USA)

Anne Zajicek

•NICHD (USA)

IRDiRC Scientific Secretariat

In place at Inserm US14, at the Rare DiseasePlatform, Paris, France

FP7 contract for 6 years since October 2012: « Support IRDiRC »

Management of the network / assistance

to Executive Committee, Scientific Committees and Working Groups

Management of the website: http://www.irdirc.org/

33

34

The Canadian FORGE project

An example of a successful national rare disease research consortium,

proving that collaboration produces results

36

Kym Boycott, PhD, MD, FRCPC, FCCMGClinical Geneticist, Department of Genetics

Investigator, Children’s Hospital of Eastern Ontario Research InstituteAssociate Professor, Department of Pediatrics, University of Ottawa

1 Gene per WeekTranslating Discoveries to the

Care of Patients with Rare Diseases

FORGE Canada Consortium

Objectives Rapidly identify genes for rare pediatric single-

gene disorders 2 years April 2011 to March 2013 Total funding level ~$5M

Establish a sustainable national consortium focused on rare disorders

FORGE Clinical Network

Dr. Gudrun Aubertin

Dr. Jan FriedmanDr. Francois Bernier

Dr. Ordan Lehman

Dr. Bridget Fernandez

Dr. Sarah Dyack

Dr. Edmond Lemire

Dr. Albert Chudley

Dr. Victoria SiuDr. Malgorzata Novaczyk

Dr. Linda Kim

Dr. Peter Kannu

Dr. David ChitayatDr. Rosanna Weksberg

Dr. Marjan Nezarati

Dr. Kym Boycott

Dr. Sandra Farrell

Dr. Jacques MichaudDr. Sebastian Levesque

Dr. Régen Drouin

Dr. Bruno Maranda

Toronto

Montreal

21 Sites80 Physicians50 Scientists

FORGE Clinical Network

Map of International Collaborators

One Gene per Week

110 disorders solvedApril 2011 – March 2013

184Disorders

60% solved45% novel5% mechanism50% diagnosis

40% unsolved

1/3 no plausible variants

2/3 too manyvariants

The rule of 1/3

1/3 novel genes

1/3 diagnosis in known

disease gene

Atypical phenotypes

Conflation of 2 diseases

New mechanisms

1/3 need more work

2014 ACTION PLAN: ADOPT AND PROMOTE STANDARDS FOR INTEROPERABILITY / DATA SHARING

43

Workshop on Terminologies for RD –Paris, 12 September 2012

Many terminologies in use to describe phenomes - No interoperability

Joint EuroGenTest and EUCERD workshop

Organized by Ségolène Aymé

Agreement to define a core set of terms common to all terminologies and a methodology

Core set identified by cross referencing

HPO

PhenoDB

Orphanet

UMLS: MeSH, MedDRA, SnoMed CT

LDDB

Elements of morphology

44

Adoption of a core set of >2,300 terms common to all terminologies

Workshop of validation, Boston

21-22 October 2013 Workshop supported by HVP and

EuroGenTest

Organized by Ada Hamosh

Expert review of the initial proposal

Selection of 2,370 terms

Decision to propose them for adoption by all terminologies

Establishment of the International Consortium for Human Phenotype Terminologies – ICHPT

Publication on the IRDiRC website with definitions from

HPO

Elements of morphology

Standardization of Phenotype Ontologies

Workshop SYMPATHI, 19 Apr 2013, Dublin Organized by IRDiRC, supported by the University of Dublin, FORGE and EuroGenTestConclusion: Adopt HPO & ORDO & cross-reference with OMIM

PhenoTips and PhenomeCentral

Repository of data

Hub for data sharing

CareforRare, RDConnect

NIH undiagnosed patients

46

Adoption of a core set of >2,300 terms common to all terminologies

ClinVar and ICCG

Public archive of variants and assertions about significance

NCBI resource

Decipher Database of Chromosome imbalances and phenotypes

Using Ensemblresources

Sanger Institute

Wellcome Trust

Fruit trees and genes…

Levels of complexity

Matchmaker Workshop

API – Application Programming Interface

BostonOctober 2013

Genome-Phenome

Matchmaker

Two WGs to look at:1) levels of data sharing2) API to connect discoverable data – operational fall 2014

– Matchmaker 1.0

Matchmaker Pro – 2015-2016

A list of databases to use for data deposition and that can be connected by Matchmaker needs to be developed and made available on the IRDiRC website – mid 2014

Thank you!

51