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Genetic Discovery of Drug TargetsGenetic Discovery of Drug Targets

Most drugs block the activity of proteinsMost drugs block the activity of proteins Genetic models of drugs (“Drug surrogates”)Genetic models of drugs (“Drug surrogates”)

• Protective allelesProtective alleles• Loss of function mutations that mimic desired drug activity Loss of function mutations that mimic desired drug activity

(“drug surrogate mutations”)(“drug surrogate mutations”)

Genetically-identified targets are superiorGenetically-identified targets are superior• Strong proof of target validity- in humansStrong proof of target validity- in humans• Significantly higher probability of success in clinical trialsSignificantly higher probability of success in clinical trials

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Example 1: A Target for OsteoporosisExample 1: A Target for Osteoporosis

Sclerosteosis: pathology Sclerosteosis: pathology due to growth of dense, due to growth of dense, strong bonesstrong bones

Isolated populationIsolated population Recessive mutation Recessive mutation

• Loss of functionLoss of function

Normal Sclerosteosis

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Genetic Mapping to 17q21Genetic Mapping to 17q21

Shared Disease Haplotype in blackShared Disease Haplotype in black

Genetic mapping of 22 families Genetic mapping of 22 families defined a region of chromosome 17q21defined a region of chromosome 17q21

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Candidate Gene Identification by SequencingCandidate Gene Identification by Sequencing (Circa 1997)(Circa 1997)

•Isolated a set of 30 clones that spanned 3 megabasesIsolated a set of 30 clones that spanned 3 megabases•Identified 150 candidate genesIdentified 150 candidate genes•Sequenced the candidate genes in patients and controlsSequenced the candidate genes in patients and controls

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Functional Confirmation of MutationFunctional Confirmation of Mutation

Single base change in one Single base change in one gene gene

Found a different change Found a different change in the same gene in a in the same gene in a different populationdifferent population

Built four different Built four different versions of the genes to versions of the genes to confirm that the mutations confirm that the mutations blocked its functionblocked its function

Two mutations were not Two mutations were not present in 360 controls present in 360 controls

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““Sclerostin” is a Cystine Knot ProteinSclerostin” is a Cystine Knot Protein

Secreted protein that Secreted protein that resembles BMP antagonists resembles BMP antagonists DAN and NogginDAN and Noggin

Part of the normal regulation Part of the normal regulation of bone metabolismof bone metabolism

Antibodies to Sclerostin can Antibodies to Sclerostin can block its activityblock its activity

Variations in the gene affect Variations in the gene affect bone density in the general bone density in the general populationpopulation

Noggin proteinNoggin protein(family member)(family member)

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Patent on Antibodies That Block Sclerostin Patent on Antibodies That Block Sclerostin

We Claim:We Claim:

1. A method for altering 1. A method for altering bone density comprising bone density comprising administering to an administering to an individual a individual a therapeutically effective therapeutically effective amount of antibody that amount of antibody that binds to (sclerostin) binds to (sclerostin) peptide and increases peptide and increases bone density...bone density...

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Anti-Sclerostin Antibody in Clinical TrialsAnti-Sclerostin Antibody in Clinical Trials

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Example 2: Protective Allele in Crohn’s Example 2: Protective Allele in Crohn’s

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IL23 Pathway as a Drug Development TargetIL23 Pathway as a Drug Development Target

Loss-of-function alleles lead to reduced disease Loss-of-function alleles lead to reduced disease riskrisk

Similar genetic effects in psoriasis, rheumatoid Similar genetic effects in psoriasis, rheumatoid arthritis and ankylosing spondalytisarthritis and ankylosing spondalytis

Several patent applications for IL-23 antibodies Several patent applications for IL-23 antibodies and antagonistsand antagonists• Identified as a target before the mapping data was availableIdentified as a target before the mapping data was available

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IL-23 Antagonist in Clinical TrialsIL-23 Antagonist in Clinical Trials

This work pre-dated the genetic mapping resultsThis work pre-dated the genetic mapping results

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““Drug Surrogate” MutationsDrug Surrogate” Mutations

Discovery of the sclerosteosis mutations directly Discovery of the sclerosteosis mutations directly led to the development of a drug for osteoporosisled to the development of a drug for osteoporosis

Drug surrogate mutationsDrug surrogate mutations• Modulate disease characteristicsModulate disease characteristics• Loss-of-function = small molecule or antibodyLoss-of-function = small molecule or antibody• Gain-of-function = therapeutic proteinGain-of-function = therapeutic protein

Human genetics yields superior targetsHuman genetics yields superior targets• Human proof-of-principle before clinical trials are startedHuman proof-of-principle before clinical trials are started• Superior to animal modelsSuperior to animal models• Clinical trials are easier to justify if you know the answer Clinical trials are easier to justify if you know the answer

before you startbefore you start

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Mapping StrategyMapping Strategy

Use clinical data and genealogy information to Use clinical data and genealogy information to identify individuals and pedigreesidentify individuals and pedigrees

Sequence to identify mutationsSequence to identify mutations• Recent proof of principle at ISB and other groupsRecent proof of principle at ISB and other groups

Develop new genetic and statistical tools to Develop new genetic and statistical tools to maximize the value of the datamaximize the value of the data• Tools to combine data from multiple rare, uncharacterized Tools to combine data from multiple rare, uncharacterized

mutationsmutations

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ExamplesExamples

Low or high lipid levels without diseaseLow or high lipid levels without disease Fat taste sensitivity and BMIFat taste sensitivity and BMI Type II diabetes without sequelaeType II diabetes without sequelae

• Retinopathy, neuropathy, nephropathy and arteriosclerosisRetinopathy, neuropathy, nephropathy and arteriosclerosis

Cell-based immunological screensCell-based immunological screens Obesity without Type II DiabetesObesity without Type II Diabetes Non-pathological physiological abnormalitiesNon-pathological physiological abnormalities

Changing the Economics of Drug DevelopmentChanging the Economics of Drug Development

The biggest cost of drug development is the cost The biggest cost of drug development is the cost of failure of failure • Development costs for 90% of targets that fail in clinical trials Development costs for 90% of targets that fail in clinical trials

amortized over the few successful drugsamortized over the few successful drugs

Use human genetic variation to identify and Use human genetic variation to identify and validate targets that will not fail in clinical trialsvalidate targets that will not fail in clinical trials• All of the significant medical and scientific risks with AMG All of the significant medical and scientific risks with AMG

785 (the SOST antibody) were answered in Phase I785 (the SOST antibody) were answered in Phase I• With current technology, we could go from a family pedigree With current technology, we could go from a family pedigree

like sclerosteosis to an antibody ready for Phase I trials for a like sclerosteosis to an antibody ready for Phase I trials for a few million dollarsfew million dollars

This approach requires access to collaborators This approach requires access to collaborators with linked medical and genealogical recordswith linked medical and genealogical records

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