Epigenetic Therapeutics: Mechanisms, Modalities and Outcomes for Human Health

Epigenetic Therapeutics: Mechanisms, Modalities and Outcomes for Human Health

Marc Muskavitch

Sr. Director, Epigenetics

September 10, 2014

2.

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

3.


RNA BiologyLong Noncoding RNAs

Micro RNAsRNA Editing

Chromatin BiologyHistone Writers/Erasers

Histone Readers/RemodelersDNA Methylation

Wahlestedt Nat Rev Drug Disc 2013Arrowsmith et al Nat Rev Drug Disc 2012

4.


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

5.


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 2004Yandell The Scientist 2014

6.


Open (active/transcribed) and closed (inactive/ nontranscribed) configurations of chromatin

Klug et al 2011

7.


Klug et al 2011

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

8.


Klug et al 2011

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 degradationmessenger RNAs and noncoding RNAs, complementary to the bound siRNA

Anti-viral defense system

9.

Diseases associated with mutations in epigenetic modifiers

Gos Acta Neurobiol Exp 2013

10.




Arrowsmith et al Nat Rev Drug Disc 2012

11.Arrowsmith et al Nat Rev Drug Disc 2012

HDAC and sirtuin inhibitors in clinical development

12.

Long noncoding RNAs implicated in human disease

Wahlestedt Nat Rev Drug Disc 2013

13.




Wahlestedt Nat Rev Drug Disc 2013

14.

Anti-sense RNA therapeutic pipeline at Isis Pharmaceuticals

http://www.isispharm.com/Pipeline/index.htm

15.


16.


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)

17.


Company Target Indication Molecule/ ID Status

Acetylon Pharmaceuticals HDAC6 Lymphoma, Multiple Myeloma ACY-1215 Phase I/II

Constellation EZH2BET

LymphomaLymphoma SM CPI-0610

PreclinicalPhase I

Epizyme DOT1LEZH2

Leukemia NHL

EPZ-5676EPZ-6438

Phase I/IIPhase I/II BCL

GlaxoSmithKline LSD1BET

SCLC, LeukemiaCancer

GSK2879552GSK525762

Phase IPhase I

Eisai (with Epizyme) EZH2 BCL E7438 Phase I/II

Salarius LSD1 Ewing’s Sarcoma SP-2528 Preclinical

Zenith Pharmaceuticals BET Hematologic Cancers ZEN-3365 Preclinical

Drug development pipeline (in part)

18.


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)

19.

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


20.


DNMTi approved by FDA for clinical use• Azacitidine (Pharmion Corporation)• Decitabine (InnoPharma) Myelodysplastic syndrome DNMTi side effects/liabilities• Neutropenia• Thrombocytopenia• Anemia• Pneumonia• Fatigue

21.


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)

22.


Common drugs with known/possible epigenetic impacts

Csoka and Szyf Med Hypoth 2009

23.


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

24.






Wahlestedt Nat Rev Drug Disc 2013Arrowsmith et al Nat Rev Drug Disc 2012

25.


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

Epigenetic Therapeutics: Mechanisms, Modalities and Outcomes for Human Health

Marc Muskavitch

Sr. Director, Epigenetics

September 10, 2014

Documents

Epigenetic Therapeutics: Mechanisms, Modalities and Outcomes for Human Health