Nessa Carey

The Challenges in Turning Epigenetic Hope into Clinical Reality

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. 0 All Hail The Double Helix

“Today we are learning the language in which God created life”

“The outstanding achievement .. in terms of human history”

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. But There Must Be More

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. How Do We Know?

EYE OF SCIENCE / SPL / BARCROFT MEDIA

Where genetic identity ≠ phenotypic identity…..

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. DNA Is Not A Lonely Molecule

Lodish et al., 2000

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. Licensed Epigenetic Drugs (1) DNA Methyltransferase Inhibitors

NH2

N N

NH O

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. 13 Licensed Epigenetic Drugs (2) Histone Deacetylase Inhibitors

O

NH OH NH O

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. 14 Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. Reassuring

Clinicalwww.clinical trials trials.gov Search on “epigenetic” n=101

PubMed

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. Breaking It Down

Clinical trials Clinical trials

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. 17 Not So Reassuring

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. 18 How Hard Can It Be?

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. 19 The Hero Who Will Save Us....

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. 20 The Thought Experiment

• Generate a straightforward question

• Generate a huge amount of data relevant to the question

• Feed into the Systems Biology “machine”

• Do we get a useful answer?

• Two questions for the price of one

• DNMTi and MDS?

• HDACi and CTCL?

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. 21 Not Without Hope

• EZH2 • DOT1L

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. 22 An Embarrassment of Riches?

Richon et al., Chem Biol Drug Des 2011; 78: 199–210 Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. And It’s Not Getting Any Easier......

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. 24 A Return To Tradition?

Biased Phenotypic Screening Random Phenotypic Screening • siRNA • Random compounds

• Tool compounds

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. 25 Playing Nicely Together.....

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. 26 From Little Acorns....

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. 27 Orphan Diseases

• Potentially very powerful test beds for epigenetic therapies

• The disease need not be caused by a defect in an epigenetic pathway per se

• May generate data that can be expanded from the orphan disease to the wider population e.g. HD into more general neurodegenerative disorders

• Address many of the dosing issues that are possibly key to the success of epigenetic therapies

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. 28 Learning More From Clinical Trials

• Pulsatile dosing • Selectivity – how big an issue really? • Toxicity • Off-target • Biomarkers • Sub-MTD dosing in • Drug combinations • PK/PD relationships

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. 29 Toxicity Of Epigenetic Drugs

• Nausea • Anaemia • Thrombocytopaenia • Neutropaenia • Leukopaenia

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. 30 Not All DNA Is Created Equal

• Impossible to create mammals by fusing two sperm nuclei or two egg nuclei in an enucleate egg • Seems odd, given that two sperm or two eggs would have exactly the same DNA as an egg and a sperm • Mammalian DNA is marked with its parent-of-origin • Only occurs at a relatively small number of specific genes • Process known as imprinting • Probably evolved as a mechanism to balance out the competing drivers from maternal and paternal developmental agendas • The information on parent-of-origin is not transmitted in the DNA sequence • It is transmitted by chromatin modifications, usually DNA methylation, that regulate expression of genes from specific chromosomal loci

• Shows that epigenetic information can be transmitted from one generation to the next

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. 31 Alcohol And Epigenetics

╬

Exposure of a dark agouti mother to alcohol led to a greater proportion of dark offspring, with increased DNA methylation at the agouti-associated retrotransposon.

Environmental agents can alter the transmission of epigenetically-mediated traits.

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. Kaminen-Ahola et al., PLoS Genet. 2010 32 Fathers And Food And Epigenetics

These effects, just like those found in the alcohol-treated agouti mice, occur at too high a rate to be due to mutation.

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. 33 Hmmm

• Most of the compounds known to have epigenetic effects are not direct inhibitors of epigenetic

• In some cases they are probably working by altering the availability of e.g. methyl donors

• In other cases we have no real idea how they cause epigenetic alterations

• There are hints from human systems that we may be susceptible to similar effects . Foetal alcohol syndrome . Dutch hunger winter . Overkalix feast or famine

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. 34 Here To Stay

• Publications • Clinical Trials • Investment Funding • Pharma Funding • Government Funding • Charity Funding • CROs

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. 35 Rationally, What Do We Need?

• Better and more standardised model systems • Greater availability of tool compounds • A way of changing data into information • Increased use of pre-competitive collaborations • Integrated patient data sets • Dialogue with regulatory authorities • Avoidance of group-think

• What’s the most important lesson from the history of epigenetic drug discovery?

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. 36 With Thanks To

Pfizer Academia Mark Bunnage Harvard Anne Phelan MGH Caroline Benn University of Cambridge Rob Rollins University of Edinburgh Valeria Fantin University of Pennsylvania Denis Patrick USC Sally John Babraham Institute Kevin Lee Rachel Grimley

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. 37