Transcript Epigenetic Therapeutics: Mechanisms, Modalities and Outcomes for

Epigenetic Therapeutics: Mechanisms,
Modalities and Outcomes for Human Health
Marc Muskavitch
Sr. Director, Epigenetics
September 10, 2014
Epigenetic Therapeutics
Epigenetics (“over” or “upon” - genetics) is
the study of (heritable) changes in gene function that depend on
mechanisms other than changes in DNA sequence
Consensus 2013
“an epigenetic trait is a stably heritable phenotype resulting from changes
in a chromosome without alterations in the DNA sequence”
Berger et al., 2008
“the study of the mechanisms of temporal and spatial control of gene
activity during the development of complex organisms”
Holliday, 1990
‘‘the branch of biology which studies the causal interactions between
genes and their products which bring the phenotype into being”
Waddington, 1942
2.
Epigenetic Therapeutics
Chromatin Biology
RNA Biology
Histone Writers/Erasers
Histone Readers/Remodelers
DNA Methylation
Long Noncoding RNAs
Micro RNAs
RNA Editing
Arrowsmith et al Nat Rev Drug Disc 2012
3.
Wahlestedt Nat Rev Drug Disc 2013
Epigenetic Therapeutics
Epigenetics and disease
• Mutations in genes encoding epigenetic modifiers
(e.g., HDAC, HAT, DNMT, MECP) and ncRNAs
are associated with human disease
• Antagonists of histone deacetylases are moving into the clinic
• Anti-sense RNA-based therapies are moving into the clinic
Ensemble therapeutics
• Epigenetic therapeutics can be considered “ensemble
therapeutics” because drugs directed against an epigenetic
function will affect the expression/function of multiple targets
• Chromatin writers/erasers/readers interact with multiple sites
• Antisense RNAs target multiple mRNAs and/or ncRNAs
4.
Epigenetic Therapeutics
Histones and DNA
are modified by a
variety of enzymes
• HAT: histone
acetyl transferase
• HDAC: histone
deacetylase
• HMT (KMT): histone
methyltransferase
• HDM (KDM): histone
demethylase
• DNMT: DNA
methyltransferase
Peterson and Laniel Curr Biol 2004
Yandell The Scientist 2014
5.
Epigenetic Therapeutics
Open (active/transcribed) and closed (inactive/
nontranscribed) configurations of chromatin
Klug et al 2011
6.
Epigenetic Therapeutics
miRNA regulation and RNA
interference lead to targeted RNA
degradation
microRNA (miRNA) precursors are
transcribed in the nucleus, then
processed into mature miRNAs by Dicer
miRNAs bind to the RNA-induced
silencing complex (RISC) and catalyze
degradation of messenger RNAs and
noncoding RNAs
Klug et al 2011
7.
Epigenetic Therapeutics
Dicer cleaves double-strand
RNA (including double-strand
RNA viruses) into 21 nucleotide
fragments
These 21 nt silencing RNAs
(siRNAs) bind to the
multicomponent RISC
RISC targets for degradation
messenger RNAs and
noncoding RNAs,
complementary to the bound
siRNA
Klug et al 2011
Anti-viral defense system
8.
Diseases associated with mutations in epigenetic modifiers
Gos Acta Neurobiol Exp 2013
9.
Epigenetic Therapeutics
Chromatin Biology
Histone Writers/Erasers
Histone Readers/Remodelers
DNA Methylation
Arrowsmith et al Nat Rev Drug Disc 201210.
HDAC and sirtuin inhibitors in clinical development
Arrowsmith et al Nat Rev Drug Disc 2012
11.
Long noncoding RNAs implicated in human disease
Wahlestedt Nat Rev Drug Disc 2013
12.
Epigenetic Therapeutics
RNA Biology
Long Noncoding RNAs
Micro RNAs
RNA Editing
Wahlestedt Nat Rev Drug Disc 2013
13.
Anti-sense RNA therapeutic pipeline at Isis Pharmaceuticals
14.
http://www.isispharm.com/Pipeline/index.htm
Epigenetic Therapeutics
15.
Epigenetic Therapeutics
Modalities for epigenetic therapies
Small molecules: antagonists and agonists of epigenetic modifiers
(oral, subcutaneous, intravenous)
Biologics (antibodies, factors): inhibitors or substitutes for
epigenetic modifiers (oral, subcutaneous, intravenous)
Antisense oligonucleotides (ASOs): reduction of RNA levels by
RNA interference (subcutaneous, intravenous, intrathecal)
Cell and gene therapy: genome editing (ZFN, TALEN, CRISPR),
antisense, noncoding or coding RNA delivery (viral vectors)
16.
Epigenetic Therapeutics
Drug development pipeline (in part)
Company
Acetylon
Pharmaceuticals
Target
Indication
Molecule/ ID
Status
HDAC6
Lymphoma, Multiple Myeloma
ACY-1215
Phase I/II
EZH2
BET
Lymphoma
Lymphoma
SM CPI-0610
Preclinical
Phase I
DOT1L
EZH2
Leukemia
NHL
EPZ-5676
EPZ-6438
Phase I/II
Phase I/II BCL
GlaxoSmithKline
LSD1
BET
SCLC, Leukemia
Cancer
GSK2879552
GSK525762
Phase I
Phase I
Eisai (with Epizyme)
EZH2
BCL
E7438
Phase I/II
Salarius
LSD1
Ewing’s Sarcoma
SP-2528
Preclinical
BET
Hematologic Cancers
ZEN-3365
Preclinical
Constellation
Epizyme
Zenith
Pharmaceuticals
17.
Epigenetic Therapeutics
HDACi approved by FDA for clinical use
• Vorinostat
Cutaneous T cell lymphoma (Merck)
• Romedepsin
Cutaneous T cell lymphoma (Gloucester Pharmaceuticals)
• Belinostat
Peripheral T cell lymphoma (Spectrum Pharmaceuticals)
HDACi side effects/liabilities
• Fatigue
• Nausea/diarrhea
• Thrombocytopenia
• Cardiotoxicity (prolonged QT interval, hERG effects)
18.
Epigenetic Therapeutics
HDAC6-selective inhibitor in clinical trials
• Ricolinostat
(Acetylon Pharmaceuticals)
Indications
• Multiple myeloma
With bortezomib or lenalidomide, and dexamethasone
• Relapsed-and-refractory multiple myeloma
With pomalidomide and dexamethasone
• Relapsed/refractory lymphoid malignancies
19.
Epigenetic Therapeutics
DNMTi approved by FDA for clinical use
• Azacitidine (Pharmion Corporation)
• Decitabine (InnoPharma)
Myelodysplastic syndrome
DNMTi side effects/liabilities
• Neutropenia
• Thrombocytopenia
• Anemia
• Pneumonia
• Fatigue
20.
Epigenetic Therapeutics
ASOs approved by FDA for clinical use
• Mipomersen (ApoB) (Isis Pharmaceuticals/Genzyme)
Familial hypercholesterolemia
• Fomivirsen (Isis Pharmaceuticals/Ciba Vision Corporation)
Cytomegalovirus retinitis
ASO side effects/liabilities
• Prolonged activated partial thromboplastin time (aPTT)
• Activation of alternative complement pathway
• Pro-inflammatory reactions
• Elevation of hepatic enzymes (ALT, AST)
21.
Epigenetic Therapeutics
Common drugs with known/possible epigenetic impacts
Csoka and Szyf Med Hypoth 2009
22.
Epigenetic Therapeutics
Epigenetic drugs and pregnancy/breastfeeding
• Should epigenetic therapeutics be avoided during
conception, pregnancy and breastfeeding?
• For vorinostat, romedepsin, belinostat:
US FDA Pregnancy Category D: There is positive evidence of
human fetal risk based on adverse reaction data from
investigational or marketing experience or studies in humans,
but potential benefits may warrant use of the drug in pregnant
women despite potential risks.
A decision should be made to discontinue breastfeeding or
discontinue the drug, taking into account the importance of the
drug to the mother.
Csoka and Szyf Med Hypoth 2009
23.
Epigenetic Therapeutics
Chromatin Biology
RNA Biology
Histone Writers/Erasers
Histone Readers/Remodelers
DNA Methylation
Long Noncoding RNAs
Micro RNAs
RNA Editing
Arrowsmith et al Nat Rev Drug Disc 2012
24.
Wahlestedt Nat Rev Drug Disc 2013
Epigenetic Therapeutics
Epigenetics and disease
• Mutations in genes encoding epigenetic modifiers
(e.g., HDAC, HAT, DNMT, MECP) and ncRNAs
are associated with human disease
• Antagonists of histone deacetylases are moving into the clinic
• Anti-sense RNA-based therapies are moving into the clinic
Ensemble therapeutics
• Epigenetic therapeutics can be considered “ensemble
therapeutics” because drugs directed against an epigenetic
function will affect the expression/function of multiple targets
• Chromatin writers/erasers/readers interact with multiple sites
• Antisense RNAs target multiple mRNAs and/or ncRNAs
25.
Epigenetic Therapeutics: Mechanisms,
Modalities and Outcomes for Human Health
Marc Muskavitch
Sr. Director, Epigenetics
September 10, 2014