ERRIN Health WG Meeting: Personalised Medicine: Opportunities for European Regions

Brussels, 2019 October 21.

Navarra 1,000 Genomes Project (NAGEN 1000): Anexample of a Regional Pilot Project for theImplementation of Personalised Genomic Medicine inthe Healthcare

Angel AlonsoNAGEN Project Director.

> Diagnosis of diseases of genetic cause .

> Characterization of genetic variants related to personal risk.

> Identification carriers of serious genetic diseases.

> Identification of genetic variants responsible for pharmacological response.

> Stratification of patients for care management.

Genomic Medicine applications:

Context

“Implementation of the use of information derived from Whole Genome Sequencing as aclinical tool for personalised medicine in Navarre Public Health Service (SNS)”

- Translational research, innovation & genomics industry development

PATIENTSHEALTHCARE PROFESSIONALS

TECHNOLOGYRESEARCH

Sequencing 1,000 whole genomes from SNS patients with rare diseases (>200 RD catalogue).

Aims NAGEN 1000

Implementation Science Approach

> "It takes 17 years on average to convert the results of the research to benefit the patient" David Chambers, director Implementation science National Cancer Institute.

> “It is the method to promote the integration of research findings in health care” (NIH, 2016).

> Tools: Identification of Barriers and Pilot projects.

Methodology

Tech

no

logy

• No high throughput genome sequencing facility.

• No bioinformatics platforms/staff.

• No preclinical evidence of the effectiveness of interventions.

ICT

• No adequate infrastructures designed to genomic data storage.

• Absence of supercomputing for genomic data processing.

• EHR inadequate to connect with genomics.

ELSI

• Concerns over consent and privacy of genomic data.

• No adequate legal framework.

• Ownership of genomic information for research and marketing purposes.

Edu

cati

on

& A

war

en

ess

• Resistance to the change of routine medical practices.

• Inadequate Health professionals profiles

• Public unawareness

Sust

ain

abili

ty • Misaligned financial incentives

• Need to align with the future burden of disease and health

• No national strategy on PM

Local barriers for Genomic Medicine Implementation in Navarra (NAGEN 1000 project):

Results: Barriers

> Optimized use of pre-existing public infrastructures

➢CNAG-CRG is a non-profit SEQUENCING

PLATFORM funded by the Spanish Ministry of Science, Innovation and Universities and the Catalan Government .

➢CIBERER-BIER, is a transversal

BIOINFORMATICS PLATFORM funded by the Spanish Ministry of Science, Innovation and Universities and the Andalucia Government.

NAGEN

CNAG-CRG

CIBERER-BIER

Results: Key Actions for this implementation

SAMPLES SEQUENCING PRIORIZATION INTERPRETATION

+ Consent +

Supercomputing BioinformaticsProcessing

Health Care

Research

Results: Key Actions for this implementation

https://www.nagen1000navarra.es/:

> Education and training

> Dissemination

> Pre-clinical evidence

> Electronic Health Records (EHR)

> ICT

> Ethical, Legal and Social Implications (ELSI)

> Marketing of genomic Services

> Subjects and recruitment design

> Alignment with other strategies

Results: Key Actions for this implementation

18SpecailitityChampions

NAGEN monographic symposiumS (CHN, NB) 2

Hospital Clinical sessions CHN 1

Interhospitalary presentations (Comarcal, Primary) 3

Services clinical sessions 9

National Scientific Communications (CIBER,CNAG) 3

International Scientific Communications (British Society Genetics) 1

National Strategic Communications (Spanish Senate, RocheInstitute, Sapanish Hospital CEOs meeting )

2

International Strategicc Communications (DG Sante, EC) 1

International Concerted actions(CEIN, Pirepred) 2

General Public information (National Science Week, RD Patientassociation)

2

Press conferences and media difusion (news papers, radio, TV) 1

Website 1

IC PerMed Best Practice in Personalised Medicine Award 2018 1

> > ICT

➢ 4 calculating nodes (IBM POWER 9 superprocessor).

➢ Infiniband transmision 100Gb/s

Optimized use of pre-existing public infrastructures

> Pre-clinical evidence

NAGEN

EHR adaptation

HC

Storage

Super

computer

Results: Key Actions for this implementation

Results: Key Actions for this implementation

Ethical, Legal and Social Implications (ELSI)

Under the Health Regulatory local Authority

➢ WGS is part of the patient’s medical record.

➢ For regulatory porpoises it is part of the

Clinical Biobank under the regulations of

the Patient Protection Act.

➢ For Research porpoises a Genome Library is

to be founded with similar regulations and Governance as to biobanks.

ELSI

WGS

EHR

Genome

Library

Clinical

Biobank

Secondary Findings

SF Disease risk

SFReproductive risk

SFPharmacogenetic

> Pre & Clinical Evidence

Results: Key Actions for this implementation

Pertinent Findings

Candidate

results

Research

Diagnosticresults

Referrals370

Recruitment624g (268f)

Sequenced431g (179f)

Analysed375g (148f)

Secundary resultsDisease risk = 2% (8/352)Reproductive = 4% (15/362)Pharmacogen = 100% (388/388)

Primary/Diagnostic results

> Pre & Clinical Evidence

Results: Key Actions for this implementation

Diagnoses

33% (48)

Strong23% (33)

Mild18% (26)

No diagnosis26% (37)

> Clinical Evidence: Pertinent Findings

> Optimized use of pre-existing public infrastructures

> Electronic Health Records (EHR)

➢ ICT> Ethical, Legal and Social Implications (ELSI)

➢ Marketing of genomic Services

➢ Subjects and recruitment design

30%

30%10%

30%

33%

2518

26

Diagnosis achieved

Strong candidate diagnosis

Mild candidate diagnosis

No diagnosis

Results: Key Actions for this implementation

OMIM Asociado

617799. MENTAL RETARDATION, AUTOSOMAL DOMINANT 54; MRD54159440. CHARCOT-MARIE-TOOTH DISEASE CMT1B, CMT2I, CMT2J, DEJERINE-SOTTAS, CHN, ROUSSY-LEVY DYSTASIA

601592. Myasthenic syndrome, congenital, 11, associated with acetylcholine receptor deficiency 607208 EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 6; EIEE6

117550. SOTOS SYNDROME 1; SOTOS1 613237 FOCAL SEGMENTAL GLOMERULOSCLEROSIS 5; FSGS5

Sin descripción en OMIM 607060. PARKINSON DISEASE 8, AUTOSOMAL DOMINANT; PARK8

617721 NEURONOPATHY, DISTAL HEREDITARY MOTOR, TYPE IX; HMN9 613287 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2N; CMT2N

108500 EPISODIC ATAXIA, TYPE 2; EA2 600116 PARKINSON DISEASE 2, AUTOSOMAL RECESSIVE JUVENILE; PARK2

605130, WIEDEMANN-STEINER SYNDROME; WDSTS 109150. MACHADO-JOSEPH DISEASE; MJD

611431. LEGIUS SYNDROME611067. SPINAL MUSCULAR ATROPHY, DISTAL, AUTOSOMAL RECESSIVE, 4; DSMA4

617450. INTELLECTUAL DEVELOPMENTAL DISORDER W. Intellectual Disability Syndrome associated to PPM1D 260400. SHWACHMAN-DIAMOND SYNDROME 1; SDS1

169500 LEUKODYSTROPHY, DEMYELINATING, ADULT-ONSET607721 NOONAN SYNDROME-LIKE DISORDER WITH LOOSE ANAGEN HAIR 1; NSLH1

300894 NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 5 616268 MENTAL RETARDATION, AUTOSOMAL DOMINANT 32; MRD32

614742. PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE, TELOMERE-RELATED, 1; PFBMFT1

300434. STOCCO DOS SANTOS X-LINKED MENTAL RETARDATION SYNDROME; SDSX

270450 INSULIN-LIKE GROWTH FACTOR I, RESISTANCE TO, 300172. CALCIUM/CALMODULIN-DEPENDENT SERINE PROTEIN KINASE; CASK

229600 FRUCTOSE INTOLERANCE, HEREDITARY. 148050. KBG SYNDROME; KBGS

600965. DEAFNESS, AUTOSOMAL DOMINANT 6; DFNA6 605035. WAS PROTEIN FAMILY, MEMBER 1; WASF1

604370, BREAST-OVARIAN CANCER, FAMILIAL 615485 BAINBRIDGE-ROPERS SYNDROME; BRPS

163950 NOONAN SYNDROME 1; NS1 312170 PYRUVATE DEHYDROGENASE E1-ALPHA DEFICIENCY; PDHAD

272430 CRISPONI/COLD-INDUCED SWEATING SYNDROME 1; CISS1 613720 EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 7; EIEE7

300654. FATTY ACID AMIDE HYDROLASE 2; FAAH2193700 ARTHROGRYPOSIS, DISTAL, TYPE 2A; DA2A and 618436 RTHROGRYPOSIS, DISTAL, TYPE 2B3; DA2B3

613406. WITTEVEEN-KOLK SYNDROME; WITKOS 600882. CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2B; CMT2B

604563. CHARCOT-MARIE-TOOTH DISEASE, TYPE 4B2; CMT4B2

Disease risk results

Gen Mutación EnfermedadNº

pacientes

APC c.3920T>A, p.Ile1307Lys175100. FAMILIAL ADENOMATOUS POLYPOSIS 1

6

ATP7B c.1934T>G, p.Met645Arg 277900. WILSON DISEASE 1

BRCA2c.658_659delGT p.Val220IlefsTer4 114480.BREAST CANCER

1

MUTYH c.1187G>A p.Gly396Asp608456. FAMILIAL ADENOMATOUS POLYPOSIS 2; FAP2

7

Secondary Results

Risk ConsentNumber of

patients% of cases

Disease risk 352 8 2.27%

Reproductive Risk 362 15 4,14%

Pharmacogenomics 388 388 100%

> Clinical Evidence: Secondary Findings I

Results: Key Actions for this implementation

PredictiveRisk

Reproductive Risk

Pharmacogenetics

No consentimiento 13 10 3

Consentimiento 87 90 97

0%10%20%30%40%50%60%70%80%90%

100%

Secondary Findings Consent

Results: Key Actions for this implementation

➢ Preclinical Evidence: Pediatric cancer>Fresh frozen tumour.

>Potentially actionable variants:

> Diagnostic.

> Prognostic.

> Predictive for therapy. >DNA-preserving protocols.

> Sustainability

Results: Key Actions for this implementation

> Costs

> WGS ≈ €1,000

> Full costs ≈ €3,600 per case.

> Full costs ≈ 10,800€ per RD diagnosis

(vs €19,078 Standard of Care)

> Effectivity

> Diagnoses (Time, QALYs, CBAs).

> Clinical trials.

> Secondary findings.

> New diagnoses to come?

Project goals:1. Integration of pharmacogenetic information

from NAGEN and PHARMANAGEN into theelectronic health information systems of Navarre’s Health Service (SNS-O).

1. To add a pharmacogenetic’s alert module to the electronically assisted prescriptionprogram in use at both hospital and primary care.

2. Systematic review of pharmacogeneticrecommendations:

2. Exome sequencing for pharmacogeneticpurposes:

1. Patients about to recieve drugs withpharmacogenetic recommendation.

2. Inflammatory Bowel Disease: thiopurinesand TPMT. Goal: 450 patients

3. Allogeneic hematopoietic celltransplantation: to develop a pharmacokinetic popullation model fortacrolimus including pharmacogenetic data. Goal: 50 patients

4. All the clinically relevant pharmacogenesare tested.

NAGEN- Strategy

> Aligned financial incentives

Results: Key Actions for this implementation

> Base for strategy on PM

Results: Key Actions for this implementation

Conclusions

NAGEN 1000 as a model for Personalised genomic medicine implementation in the Public Health Service:

Multidisciplinary participation of professionals and patients provides training, specialization and education.

Optimizes the use of resources and the development of new ones.

Promotes innovative ICT solutions and facilitates cooperation between sectors.

Encourages the adaptation of ethical and legal principles to new technologies.

Produces scientific findings that increase knowledge.

Contributes “real-world” clinical data for the demonstration of sustainability of PPPM approaches.

Paves the way for new implementation demonstrations.

Evidences the need for national and international PM strategies.

Navarra 1000 Genomes Project (NAGEN 1000): NAVARRABIOMED

BIOMEDICAL RESEARCH CENTREComplejo Hospitalario de Navarra (CHN)Irunlarrea 3 I 31008 Pamplona.Navarra. España. T +(34) 848 42 85 97 nagen@navarra.es

www.nagen1000navarra.esAngel Alonso. Navarrabiomed. Spain.