Download BET Inhibitors as Agents for Anti-Cancer Therapy

BET Inhibitors as Agents
for Anti-Cancer Therapy
Patricia Mucci LoRusso, D.O.
Associate Center Director – Innovative Medicine
Yale University
Patricia LoRusso, D.O.
Disclosure Type:
Consultant – Pfizer, Novartis, Astex,
Genentech, Alexion
Bromodomain: An Epigenetic Reader
A Bromodomain is a small evolutionary conserved protein-protein
interaction module that recognizes acetylated lysines
•
Bromodomains share a left
handed bundle of four α helices
linked by diverse loop regions
that confer substrate specificity
•
A hydrophobic pocket binds
acetylated lysine
•
46 diverse human proteins
contain a total of 61
bromodomains
•
frequent participants in
oncogenic translocations
Filippakopoulos et al., Cell (2012)
Confidential
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BET Protein Family Overview
BET Protein Family
• Four BET proteins (BRD2, BRD3, BRD4, BRDT)
• Bind acetylated chromatin via twin
bromodomains
• Localize to promoter and enhancer regions
• Most abundant at enhancers
• Function as co-activators to transcription
factors
• MYC in most cancers
• AR and ER
• NFkB in cancer and inflammation
• Others
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MYC
AR, ER,
NFkB…
BRD4
Epigenetic Regulation
•
•
•
Writer & eraser enzymes add/remove epigenetic modifications to
chromatin
Reader proteins regulate gene expression - bind to specific epigenetic
modifications
The BET inhibitors are drugging a fundamental class of epigenetic reader
proteins that contain bromodomains
Reader Proteins
• Bromodomain proteins
• Chromodomain proteins
• PhD domain
Writer/Eraser Enzymes
• HATs/HDACs
• Kinases/phosphatases
• DNMTs/Tet proteins
Confidential
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BET Inhibitors: A Novel Class of Oncology Drugs
• BET Inhibitors (such as JQ1) specifically
target the BET family
• Occupy the bromodomains and prevent
BET proteins from binding to acetylated
chromatin and regulating gene
expression
• Result in selective inhibition of specific
gene sets, potent growth inhibition,
senescence, differentiation and
apoptosis
• Efficacy in numerous predictive models
Filippakopoulos et al., Nature (2010)
Confidential
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Crystal Structure of JQ1 and BRD4
Mechanism for Widespread Efficacy of BET Inhibitors:
Down-Regulation of MYC
JQ1 down-regulates MYC, one of the most overexpressed and/or
amplified oncogenes
MYC is a transcriptional activator
• Activates cell proliferation, growth, and
survival pathways
• Considered a very promising yet difficult
drug target
JQ1 down-regulates MYC expression
• BRD4 occupies the MYC promoter and
enhancers
• BRD4 activates MYC expression
• JQ1 prevents BRD4 binding and decreases
Myc expression
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Widespread Efficacy Observed in
Preclinical Oncology Models
JQ1 efficacy has been observed in a wide array of cancer models
Examples in hematological and solid tumor malignancies
Glio/Medullo/Neuroblastoma
NUT Midline Carcinoma
Lung Cancer
Breast Cancer
Leukemias and Lymphomas (AML/ALL/NHL)
Multiple Myeloma
Colorectal Cancer
Prostate Cancer
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10 BRD4 Inhibitors in Clinical Development
Drug
Company
Phase
Tumor Types in Phase I
Route of
Administration
MK-8628 (OTX015)
Merck
II
AML, MDS, DLBCL, NSCLC, breast,
CRPC, pancreas, NMC
Oral
TEN-010
Tensha
I
AML/ MDS and solid tumors
Subcutaneous
GSK525762/
GSK2820151 (open
1Q16)
CPI-0610
GSK (2 drugs)
I
Broad array of heme and solid
tumors including NMC
Oral
Constellation
I
AML, MDS , NHL, HD, MM
Oral
ABBV-075
AbbVie
I
Expansions in AML, MM, breast,
NSCLC
Oral
BAY1238097
Bayer
I
HCC, lung, melanoma, lymphoma,
AML, MM, NMC
Oral
INCB054329
Incyte
I
Solid tumors + AML,NHL, MM
Oral
FT-1101
Forma
I
AML and MDS
Oral
GS-5829
Gilead
I/II
Solid tumors phase I; phase II mCRPC
combined with enzalutamide
Oral
BMS 986158
BMS
TNBC, SCLC, ovarian, +Taxol combo
Oral
I
Results of a First-in-Man Phase I Trial
Assessing OTX015, an Orally Available
BET-Bromodomain (BRD) Inhibitor, in
Advanced Hematologic Malignancies
A. Stathis1, B. Quesnel, S. Amorim, C. Thieblemont, E. Zucca, E. Raffoux,
H. Dombret, Y. Peng, A. Palumbo, N. Vey, X. Thomas, M. Michallet, C. GomezRoca, C. Recher, L. Karlin, K. Yee, K. Rezai, C. Preudhomme, T. Facon, P. Herait
1Istituto
Oncologico della Svizzera Italiana, Phase I and Lymphoma Units,
Bellinzona, Switzerland
Antitu mor Effects in Hematologic Malignancies
MTT assay, Gl50 at 72h
•
•
•
Leukemia (ALL, AML, JAK2V617F)
Lymphoma (ABC-DBCL, GBC-DBCL, ALCL, SMZL, MCL, PTCL)
Mult iple myeloma
--
M MlS - m ultiple myeloma
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vv• MYC - m u ltip le myeloma
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•
Results: Patient Accrual / Dose Escalation
• As of September 2014, dose escalation is finalized:

86 patients treated and evaluable for safety

76 evaluable for DLT: 36 AL patients and 40 OHM
Dose level
Dose
(mg/day)
AL
n=41
OHM
n=45
1
10 QD
3
5
2
20 QD
3
3
3
40 QD
4
4
4a
80 QD
4
7
4b
40 BID
8
6
5
120 QD (cont/disc*)
13 (6/7)
20 (7/13)
6
160 QD
6
0
* Continuous and discontinuous schedule optimization
OTX015 Efficacy, OHM Cohort
Dose
Level
(mg)
DLBCL
N
Patients
evaluable
Other Lymphomas/MM
N Pts (TTP days)
Objective
Response
SD
N Patients
evaluable
N Pts (TTP days)
Objective
Response
SD
10 QD
3
1
20 QD
1
0
40 QD
0
2
1 (308+)
80 QD
2
1
1 (101)
40 BID
2
120 QD
12
1 CR (131+)
1 CR (143)
1 (148)
1 (107)
1 (112+)*
1
TOTAL
20
3
3
8
1 PR (239)
1 (112)
1 (126)
1
4
*Tumor shrinkage > 40%, disappearance of glucose fixation at the subphrenic lesion major clinical benefit
Cancer Discovery, March 2016
Radiologic response of Patient 1 to OTX015/MK-8628
Histopathologic features at baseline and clinical and
radiological features at baseline and in response to treatment
with OTX015/MK-8628 in Patient 2
Constellation: CPI-0610
Phase 1 development in 3 independent studies: lymphoma, myeloma and
acute leukemia
Oral daily dosing x 14 days, followed by a 1-2 week break from treatment
Dose escalation ongoing: maximum tolerated dose not yet determined
Pharmacokinetics:
T1/2 = 10.7 hours
Pharmacodynamics:
Suppression of BET target gene (CCR1) expression at higher doses and plasma
concentrations
Principal toxicity: thrombocytopenia
CRs and PRs observed in patients with DLBCL and follicular lymphoma
Dose Dependent Reduction in CCR1 Expression
CPI-0610 Clinical Activity: DLBCL & FL
Outcomes as a Function of CCR1 suppression
CCR1 Suppression
Complete or Partial Response
Stable Disease
Progressive Disease
Total Patients Treated
No
Yes
1
2
18
21
3
3
3
9
Note: Important CCR1 Suppression Group had mean suppression of more than
50% and were populated from more than one dosing group
Clinical efficacy of the BET bromodomain inhibitor
TEN-010 in an open-label substudy with patients with
documented NUT-midline carcinoma (NMC)
G.I Shapiro1, A.Dowlati2, P.M. LoRusso3, J.P. Eder3, A. Anderson1, K.T.Do1, M.H.
Kagey4,C. Sirard4, J. E. Bradner1, S.B. Landau4
1. Dana Farber Cancer Institute, Boston, MA United States. 2. UH Case Medical Center,
Cleveland OH, United States. 3. Smilow Cancer Center/Yale, New Haven, CT, United States. 4.
Tensha Therapeutics, Cambridge, MA, United States.
TEN-010-001 Study Design
A Two Part, Phase 1, Multicenter, Open-label Study of TEN-010 Given
Subcutaneously
Part A
Part A: Dose-Escalation in Advanced Solid Tumors
•
•
•
Classic 3+3 dose escalation design
3 week on / 1 week off schedule
Enrolled 24 patients up to a maximum
dose of 0.65 mg/kg
0.03
mg/kg
0.06
mg/kg
0.10
mg/kg
0.20
mg/kg
0.30
mg/kg
0.45
mg/kg
0.65
mg/kg
Part A*
•
•
•
Classic 3+3 dose escalation design
2 week on / 1 week off schedule
Started at 0.65 mg/kg dose level
0.65
mg/kg
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0.85
mg/kg
NMC Patient 004-004
• 47 year old man with nut midline carcinoma with involvement in the right
sinonasal cavity, right orbit, sella, and right cavernous sinus
• Progression after two cycles of carboplatin, gemcitabine, and Zolinza
• Symptoms include:
• Proptosis with limited movement on initial exam
• Visual field loss in right eye
• Loss of 30 pounds
• Significant headaches
• Patient initiated at 0.65 mg/kg for 21-day cycle (14 on, 7 off) in October 2015
• After 14 days of treatment, patient has tumor mass reduction and clinical
improvements of right eye movements, headaches, and right eye proptosis
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NMC Patient 004-004 Scans (2 of 2)
•
•
Rapid clinical improvements in symptoms including improved eye movement and
reduction of headaches within 1 week of treatment
~23% reduction by RECIST in mass size at Day 14 of treatment and ~60% reduction
by volume Baseline
Day 14
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Results
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•
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33 year old man with NMC with disease in
lung, liver, cervical, thoracic and lumbar
spine, bone marrow, multiple long bones
Previous treatment with a platinum
regimen: progression
Treated with 0.45 mg/kg in 28-day cycle
Marked clinical improvement: reduction
pain, able to ambulate
Clinically reoccurred during 1 week
planned drug-holiday interruption; could
only partially generate clinical benefits with
Cycle 2
LDH Biomarker
DLBCL Patient 002-033: End of Cycle 1 Scan
Conclusions
-Multiple BET inhibitors are undergoing preclinical and clinical
investigation against multiple different tumor types
-Preliminary data show promise against various hematologic
malignancies and solid tumors
-Currently, as monotherapy, although encouraging results, efficacy
has still been somewhat limited with frequent progression after initial
response
-Multiple preclinical drug combinations have demonstrated
encouraging results that need clinical assessment