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![Page 1: Human genetics and drug discovery: the future is now Robert Plenge, MD, PhD Broad Institute Medical and Population Genetics (MPG) October 1, 2015.](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f155503460f94c2b4c7/html5/thumbnails/1.jpg)
Human genetics and drug discovery: the future is now
Robert Plenge, MD, PhD
Broad Institute
Medical and Population Genetics (MPG)
October 1, 2015
![Page 2: Human genetics and drug discovery: the future is now Robert Plenge, MD, PhD Broad Institute Medical and Population Genetics (MPG) October 1, 2015.](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f155503460f94c2b4c7/html5/thumbnails/2.jpg)
The Problem
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http://csdd.tufts.edu/
Phase II/III failures drive high cost of drug development
Rising healthcare costsdriving demand for innovative,
breakthrough therapies
HospitalCare32%
Physiciansand Clinics
20%Prescription
Drugs~10%
US Healthcare Spending
$2.9 TRILLIONin 2013
http://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-Reports/NationalHealthExpendData/NationalHealthAccountsHistorical.html
Two key challenges in drug development:high failure rate and insufficient innovation
Attrition problem Innovation problem
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The Attrition Problem
…now it is efficacy/safety
It was drug metabolism &
pharmacokinetics (DMPK)…
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The Innovation Problem
“to be Earth’s most customer-centric company, where customers can find and discover anything they might want to buy online, and endeavors to offer its customers the lowest possible prices”
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What are guiding principles?
![Page 7: Human genetics and drug discovery: the future is now Robert Plenge, MD, PhD Broad Institute Medical and Population Genetics (MPG) October 1, 2015.](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f155503460f94c2b4c7/html5/thumbnails/7.jpg)
Proof-of-concept Clinical Trials
How can we safely test therapeutic hypotheses in humans as quickly and efficiently as possible?
Causal Human Biology
Which targets, when perturbed, have a desired effect on human physiology?
Target Modulation Assays
Which biomarkers measure therapeutic modulation in
a human system?
Target ID and Validation
Lead Optimization Early Development
Prediction: increase probability of success for breakthrough therapies
Phase II-IIIClinical Trials
![Page 8: Human genetics and drug discovery: the future is now Robert Plenge, MD, PhD Broad Institute Medical and Population Genetics (MPG) October 1, 2015.](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f155503460f94c2b4c7/html5/thumbnails/8.jpg)
Technology is changing the ideal model organism for drug discovery and development
Target ID and Validation
Lead Optimization Early Development
It was…
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Today, humans are the model organism of choice for new targets and precision medicine
Target ID and Validation
Lead Optimization Early Development
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Three examples
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Proof-of-concept Clinical Trials
How can we safely test therapeutic hypotheses in humans as quickly and efficiently as possible?
Causal Human Biology
Which targets, when perturbed, have a desired effect on human physiology?
Target Modulation Assays
Which biomarkers measure therapeutic modulation in
a human system?
Target ID and Validation
Lead Optimization Early Development
Prediction: increase probability of success for breakthrough therapies
Phase II-IIIClinical Trials
![Page 12: Human genetics and drug discovery: the future is now Robert Plenge, MD, PhD Broad Institute Medical and Population Genetics (MPG) October 1, 2015.](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f155503460f94c2b4c7/html5/thumbnails/12.jpg)
Human genetics helps to identify potential drug targets to kick-start drug discovery
Disease Healthy
The key steps are:1. Map genetic differences in
those with disease vs healthy;2. Understand how these genetic
differences lead to disease;3. Develop drugs against these
targets that reverse disease processes in the population.Disease Healthy
vs
“Drug”
“Drug”
“Target”
But, tens of thousands of potential targets…
…and which one causes disease?
…and how do you perturb the target?
?
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There are anecdotal examples of human genetics leading to new drug targets (PCSK9)…
PCSK9 mutations associated with high and low LDL cholesterol levels (and heart disease risk)
…and design studies to find drugs that fix the underlying molecular defects – for example, blocking PCSK9 lowers LDL (or “bad”) cholesterol in the blood.
Lysosome
LDLR
PCSK9
LDL-C mAb
LDLRRecycling
Many genes influence cholesterol levels and risk of heart disease
AtheroscleroticPlaque Blood Flow
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…including many approved therapies, and…
Plenge, Scolnick, Altshuler, Nature Reviews Drug Discovery (2013)
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…portfolios of drug targets with human genetic support have a higher probability of success
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…portfolios of drug targets with human genetic support have a higher probability of success
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What is a genetic strategy?
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We determinedose-response in clinical trials, after many years and millions of dollars
Target ID and Validation
Lead Optimization
Early Development
Phase II-III Clinical Trials
We aspireto determine
dose-response at the time of target ID and validation
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Gene function
Hum
an P
heno
type High
Low
GOF LOF
X
X
XXX
XX
Pick a human phenotype for drug
efficacy
Identify a series of alleles with range of effect sizes in humans (but of unknown function)
![Page 20: Human genetics and drug discovery: the future is now Robert Plenge, MD, PhD Broad Institute Medical and Population Genetics (MPG) October 1, 2015.](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f155503460f94c2b4c7/html5/thumbnails/20.jpg)
Gene function
Hum
an P
heno
type High
Low
GOF LOF
X
X
XXX
XX
Pick a human phenotype for drug
efficacy
Assess biological function of alleles to estimate “efficacy” response curve
Efficacy
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Gene function
Hum
an P
heno
type High
Low
GOF LOF
Assess biological function of alleles to estimate “efficacy” response curve
Efficacy
X
X
XXX
XX Toxicity
Assess pleiotropy as proxy for ADEs
Pick a human phenotype for drug
efficacy
New target fordrug screen!
This provides evidence for the therapeutic
window at the time of target ID & validation.
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The list of genes with an “allelic series” is growing
PCSK9 low CAD risk, low LDL-C high LDL-C, high CAD risk
APP low AD, dementia risk high AD, dementia risk
SCN9A pain insensitivity neuropathy, hyperexcitability
CARD9 low IBD risk,high risk for fungal infections high IBD, AS, PSC risk
TYK2 low RA, psoriasis, SLE, MS risk,high risk for PID high T-ALL risk
IFIH1 low T1D risk,high risk for PID
high SLE risk,AG, SM syndromes
LRRK2 high PD risk
PNPLA3 low LDL-C, TG high NAFLD, NASH, PBC, HCC risk
Gene LOF GOF
… and there are further genes with protective LoF variants, for example:
SLC30A8 (T2D), NPC1L1 (CAD), APOC3 (CAD), CCR5 (HIV), MSTN (muscle), LRP5 (bone), FUT2 (norovirus resistance), KCNJ1 (HTN), CTSK (bone)
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And we are at the beginning of what will be an explosion of genetic discoveries across populations
…and a more accurate molecular understanding of human disease.
Cost of genome sequencing continues to drop rapidly…
…which results in many more human genomes being sequenced…
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KaadorieBiobank
Geisinger
NIH-AMP
Saudia Arabia Genome Project
Estonia Precision Medicine Initiative
HumanLongevity
Finnish Founder Population
INTERVAL
Kaiser-Permanente
HUNT/NTNUUK Biobank
SingaporeBiobank
Initiatives now link human genetics with clinical phenotypes in a setting for recall
Veteran’sAdministration
size/quality of genetic datasize/quality of phenotypic dataconnectivity of genetics & phenotypessetup for recalls & ph1 trials
-
+++
+ -
Ranking (estimates 10/2015):
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Proof-of-concept Clinical Trials
How can we safely test therapeutic hypotheses in humans as quickly and efficiently as possible?
Causal Human Biology
Which targets, when perturbed, have a desired effect on human physiology?
Target Modulation Assays
Which biomarkers measure therapeutic modulation in
a human system?
Target ID and Validation
Lead Optimization Early Development
Prediction: increase probability of success for breakthrough therapies
Phase II-IIIClinical Trials
![Page 26: Human genetics and drug discovery: the future is now Robert Plenge, MD, PhD Broad Institute Medical and Population Genetics (MPG) October 1, 2015.](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f155503460f94c2b4c7/html5/thumbnails/26.jpg)
What is a biomarker?• Pharmacokinetic (PK) – what the body
does to the drug• Pharmacodynamic (PD) – what the drug
does to the body
Concentration vs. Time
Effect vs.Concentration
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Genetics can bridge biomarker with clinical data, establishing a causal link for drug discovery
I DGI DG
Cvs
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Retrospective example: NPC1L1 protein (target), LDL (biomarker), coronary heart disease (POC)
Ph III clinical study in>18,000 CHD patients
• 32.7% vs 34.7% w/ primary event • HR=0.936, p=0.016• 6.4% relative risk reduction
Sequencing NPC1L1 in >7,000 patients and >14,000 controls
• 15 NPC1L1 inactivating mutations• Carriers w/ lower plasma LDL • 53% relative risk reduction
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BACE-inhibitor program in Alzheimer’s disease
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Calcoen et al (2015) NRDD99.5% failure rate!
The history of drug development for Alzheimer’s disease is not pretty – very high failure rates
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Amyloid hypothesis and Alzheimer’s disease: the role of the APP gene and BACE1 in disease initiation
Ab oligomers
Causal human biology• APP, PSEN1, PSEN2 mutations
cause FAD, increase Ab cleavage• APP-A673T variant reduces AD
risk, decrease Ab cleavage• Naturally occurring antibodies to
Ab oligomers decrease AD risk
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Therapeutic hypothesis: BACE-inhibition blocks release of toxic Ab and reduces AD progression
(3) Decrease in Ab oligomers in brain protect from AD
(2) BACE1 inhibitor mimics APP mutation and blocks first step in release of toxic A b peptides
(1) Protective APP mutation reduces BACE1 cleavage in vitro
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Ab peptide levels measured in CSF serve as a biomarker for target modulation
Drug
CSF Biomarker Does the drug engage and
modulate the target (PD)?
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Is there a dose-dependent relationship in human subjects?
Healthy Volunteers
DrugLow doseHigh dose
CSF
Alzheimer’s Patients
CSF
DrugLow doseHigh dose
BiomarkerBiomarker
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Multi-dose, healthy volunteers
CS
F Ab
40
leve
ls
Multi-dose, AD patients
Placebo (N=6 Planned)MK-8931 12 mg (N=8 Planned)MK-8931 40 mg (N=8 Planned)MK-8931 60 mg (N=8 Planned)
Baseline 0 4 8 12 16 20 24 28 32 360
40
80
100
120
160
CS
F s
Ap
p
% o
f B
as
eli
ne
Day -10 hours
I--------------- Day 7 (Hours) ----------------I
Day 7 Dose
>90% loweringPlacebo (N=10)MK-8931 10 mg (N=6)MK-8931 40 mg (N=6)
Baseline 0 4 8 12 16 20 24 28 32 360
40
80
100
120
160
CS
F A
40
%
o
f B
as
elin
e
Day -10 hours
I--------------- Day 14 (Hours) ----------------I
Day 14 Dose
MK-8931 150 mg (N=9)MK-8931 250 mg (N=9)
MK-8931 lowers Ab levels in CSF from healthy volunteers and Alzheimer’s disease patients
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A note of caution, however:
(1) Human mutations are in APP, not BACE
(2) No Mendelian randomization study with APP mutations and CSF Ab peptide levels
(3) Phase III clinical trials are now underway – the ultimate test of a therapeutic hypothesis!
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Proof-of-concept Clinical Trials
How can we safely test therapeutic hypotheses in humans as quickly and efficiently as possible?
Causal Human Biology
Which targets, when perturbed, have a desired effect on human physiology?
Target Modulation Assays
Which biomarkers measure therapeutic modulation in
a human system?
Target ID and Validation
Lead Optimization Early Development
Prediction: increase probability of success for breakthrough therapies
Phase II-IIIClinical Trials
![Page 38: Human genetics and drug discovery: the future is now Robert Plenge, MD, PhD Broad Institute Medical and Population Genetics (MPG) October 1, 2015.](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f155503460f94c2b4c7/html5/thumbnails/38.jpg)
VLPOGABAergic
neurons
Orexinneurons
Monoaminergicneurons
WakeSLEEP
Causal human biology• Autoimmune orexin deficiency in humans
results in narcolepsy• Genetic deficiency in dogs leads to narcolepsy,
and orexin pathway conserved across species
SLEEP
Acknowledgements:John Renger, Matt Kennedy, Mark Forman
Orexin Receptor Antagonists (ORAs):a new therapeutic approach to treat insomnia
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Ore
xin
A (
pg
/ml)
Time of Day
Active Inactive
=ORA
Therapeutic hypothesis: Orexin receptor antagonism (ORA) blocks wake promoting signal, enabling sleep
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• Study Design: double-blinded, placebo-controlled, 5-period
cross-over study in 20 healthy subjects
• Measurement: 8-hr PSG recording
Clinical proof-of-concept (POC) in healthy volunteers: polysomnography (PSG) sleep study
Total SleepTime
PBO 10mg 50mg 100mg430
440
450
460
TS
T (
min
)
MK-4305
Sleep EfficiencyIndex
PBO 10mg 50mg 100mg88
90
92
94
SE
I (%
)
MK-4305
96
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There are new technologies to measure clinical outcomes, including real-time patient monitoring
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We live in an amazing time…
@rplenge