Pharmacogenomics and personalized medicines

Jean-Marie Boeynaemsjmboeyna@ulb.ac.be

OUTLINE

• Definitions : SNP, omics• Personalized choice of the medicinal product• Personalized dosage of the medicinal product• Problems and first achievements• Individualized treatment of cancer• Genome-wide association studies• Technological evolution of sequencing : • « The 1,000 $ genome challenge »• Generalization of genome sequencing : • ethical, legal and practical issues

A representative sample of the slides that will be presented and discussed during the course is

displayed hereafter.

Different types of SNP

• Outside genes : no impact

• In the genes coding sequence :

• change of base but not of amino acid (cf redundancy of genetic code : GCA et GCC both code for alanine)

• change of amino acid : more or less impressive

modification of function (loss or gain)

• In the promoter region : or transcription of the gene and protein expression

• In the mRNA 3’-untranslated region : (or ) sensitivity to miRNA (that inhibit translation and destabilize mRNA).

Ome, Omics

• Genomics: all the genes• pharmacogenomics : choice of personalized medicine • nutrigenomics : choice of best diet• toxicogenomics : prediction of toxicity

• Epigenomics: all epigenetic changes in genome• Transcriptomics: all the mRNAs microarrays• Proteomics : all the proteins• Interactomics : all interactions between all proteins• Metabolomics (or metabonomics) : all metabolites • …

« Personalized medicines »based on pharmacogenomics

• Identification of genes conferring to individuals who carry them a better sensitivity to the therapeutic action of a medicine or a better tolerance (drug metabolizing enzymes, disease susceptibility factors)

• Genotyping before inclusion in a clinical trial statistical power and cost

• Simultaneous marketing of a medicinal product and availability of a genetic test to identify patients to treat

• Restriction of the market but higher price since efficacy is optimized (or adverse effects decreased) .

From personalized medicine to precision medicine

• Some are skeptical that medicine will really be personalized, while others say that physicians have always adapted treatment to their individual patients.

• Precision medicine implies that diseases are defined by underlying molecular mechanisms rather than traditional signs and symptoms.

Lancet 378 : 1678, 2011

Toward precision medicine

US National Research Council, nov 2011

Cancer Pharmacogenomics and Tumor and Germline Genomes

Wang L et al. N Engl J Med 2011;364:1144-1153.

Anticancer drugs approved by the Food and Drug Administration with labeling regarding pharmacogenomic biomarkers

Wang L et al. N Engl J Med 2011;364:1144-1153.

Lebrikizumab treatmentin asthma : efficacy related to serum periostin

Corren et al NEJM 2011

Lebrikizumab is a monoclonal

antibody that neutralizes IL-13. IL-13 induces bronchial epithelial cellsto secrete periostin. Patients with high serum periostin respond better.

DNA cleaved in fragmentsFragments fixed on beads (excess)PCR amplification in emulsion (1 bead/droplet)Transfer to multi-well (pL) slide(1 bead/well)Addition of smaller beads covered with enzymes involved in sequencing

Elongation of fragmentsSequential injection of nucleotidesIf the nucleotide is incorporated, generation of light detected by a

camera

Cost of genome sequencing

• Genome of C Venter : 100x106 $• Genome of J Watson : < 1.5x106 $• X Prize Foundation challenge : 10,000 $• Race for $ 1,000 genome : 1,000 $• Complete Genomics in 2009 : 4,400 $• Cost of the detection of a single mutation by

Belgian genetics laboratories : 300

Report freely accessibleon www.deloitte.com

Take home messages

• The business model of biopharma is changing and can now include personalized medicines.

• The major difficulty is to identify SNPs with a strong impact on treatment choice/dosage.

• Personalized medicines are making progress especially in cancer treatment, but also in asthma.

• A key element is the astounding evolution of technology with a dramatic decrease in the cost of sequencing.