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Predic'ng drug side effects with systems pharmacology
John J Irwin October 2012
Mike Keiser Nick Hodge Brian Shoichet
Drugs may cause unwanted side effects nausea vomiting fatigue dizziness dry mouth headache itching muscle pains abdominal pain blurred vision constipation diarrhea loss of appetite memory loss failure to thrive palpitations problems with coordination ringing in the ears skin rashes or hives swelling of hands or feet heart attack syncope cafe-au-lait spots ecchymosis jaundice livedo reticularis necrolytic migratory erythema
heart attack
How big a problem are we talking here? 9/30/04: Merck recalls blockbuster Vioxx
Heart aEack and stroke
$ $ $ $
$
$
$
$ $
$
$
$6 billion in claims
MRK vs S&P 500
Drug development failure rates are rising
II III
clinical FAILURES 82% 50%
by phase:
Arrowsmith, J. Nat Rev Drug Disc (Feb & May 2011).
Efficacy 51%
Strategic 29%
Safety 19%
Other 1%
Cost for 1 drug: $0.8 billion (2000) vs. $4-‐12 billion (2012)
tA 3 Test the predictions
Z-score
Freq
uenc
y
drug vs. tA
drug vs. tB
Statistical model
1 For a drug,
tA
2 Compare it to new targets
… , tB
Predic\ng side effects automa\cally
»
New targets for
marketed drugs
a Wired top-‐10 breakthrough
of 2009
Keiser, Nat. Biotech, 2007; Keiser, Nature, 2009; Lounkine & Keiser, Nature, 2012.
culprit: 5-‐HT2b off-‐target
1997 heart valve disorder
already cost Wyeth
$21 billion by 2004
What sorts of toxicity could we predict?
Off-‐target FenPhen
1996
Liver (metabolic)
Rezulin (2000) – Parke Davis – 430+ pa\ents suffered liver failures
On-‐target Vioxx (2004) – Merck – $6 billion
Setola, Roth et al, Mol Pharmacol. 2005, 68, 20-‐23.
CTX inhibits platelet aggrega\on in human
blood.
We use the networks to predict side effects
Chlorotrianisene (CTX) is a synthe\c
estrogen.
Why the stomach problems?
Lounkine, Keiser, et al. Nature, 2012
known pharmacology
new predic\ons
Similarity Ensemble Approach
We have confirmed
200+
new SEA drug-‐to-‐target predic\ons
Keiser & Setola et al, Nature, 2009. Lounkine & Keiser et al, Nature, 2012.
This is a challenge we can best solve together
Sept 2012 contract
June 2012 Nature paper
Nov 2009 Nature paper
Brian K. Shoichet lab (founders)
Rogers Bridging-‐the-‐Gap Awards
2009, 2010, & 2012 NIH Grants
