Download Problems in early drug development: PARP inhibitors

Problems in early drug development:
PARP inhibitors, an example of a
problematic class
Ruth Plummer
TAT2014
Ruth Plummer, MD, PhD
I have been involved in the clinical development of
rucaparib (AG014699, CO338) for 11 years, receiving
clinical trial support and research funding from Pfizer
GRD and Clovis Oncology
I am listed on a patent of use of AG014699
I also have received clinical trials funding for studies with
Olaparib, veliparib, iniparib, CEP-9722, BM673, E7449
I have advised on the development of olaparib, niraparib,
rucaparib
Ruth Plummer, MD, PhD
Receipt of Intellectual Property Rights / Patent
Holder: Patent of use of rucaparib (Clovis)
Consulting Fees (e.g., advisory boards): Roche,
BMS, GSK, Clovis, Vertex
I intend to reference unlabeled/unapproved uses
of drugs or products in my presentation: olaparib,
rucaparib, veliparib, niriparib
The PARP superfamily



PARP-1 is founder and best characterised
PARP-2 Identified by sequence homology to
PARP-1 catalytic domain.
Only PARP-1 and PARP-2 known to be
activated by and repair DNA breaks
PARP-1 yellow
PARP-2 grey
NAD blue
Role of PARP-1 in BER/SSBR
18 members of PARP super-family identified to date
PARP-1 abundant nuclear enzyme activated by and
binds with high affinity to DNA single and double strand
breaks via zinc fingers
PARP-1 essential for the repair of damaged bases and
single strand breaks via the Base Excision repair
pathway
PARP-1
D - Automodification
domain
A - DNA binding
domain
N
ZF
ZF
NLS
C
BRCT
F - Catalytic
domain
C
E
B - Nuclear
localisation
signal
XRCC1
The problems in clinical development
 Timelines
 Pre-clinical science ~ 15-20 years
 Clinical development ~ >10 years
 Strategy
 Dual strategy in the clinic
 Single agent
 Combination therapy
 Biomarkers
Development of the first in class PARPi – targeting the NAD+ binding
site – common to all PARPi apart from iniparib
NAD+

N
N
O
2.9
H
N
OH OH
O
N
O
P
O
P
Bond undergoing
Cleavage
-
-
O
OH O O
2.9
Glu-988
2.7
O
2.8
AG14361
Wat-52
Gln-763
*
N
NH2
OH OH
ADP ribose
Gly-863
2.8
Nicotinamide
H
+
O
N
Ser-904
* Attachment point
 Linear chain
  Branched Chain
3.2
Tyr-889
Asp-766
Based on the catalytic mechanism: analogues of the by-product, nicotinamide
O
NH2
NH
N
NH2
1980
O
O
O
1990
N
HN
OH
Newcastle
Chemists
CRUK funding
F
NH
NH
CH3
O
NH
H
1996
N
N
2001
HN
2003
Agouron
Chemists
N
OH
N
3-aminobenzamide (3AB)
Ki = 10 M
NU1025
Ki = 48 nM
NU1085
Ki = 6 nM
AG14361
Ki < 5 nM
AG 14 447
Ki < 5 nM
PARP Inhibitors in Clinical Trials
Agent
Company
Single/Combination
therapy
AG014699
(PF0367338,
CO338)
(rucaparib)
2003
Clovis/Pfizer
Combination ++/single
KU59436
(AZD2281)
(olaparib)
2005
AstraZeneca/
KuDOS
ABT-888
(veliparib)
2006
Route of
administration
Disease area
Current Clinical status
I.v. And oral
Cancer
Phase III
Single/
Combination ++
Oral
Cancer
Phase III
Abbott
Laboratories
Single/
Combination ++
Oral
Cancer
Phase III
BSI-201
(SAR 240550)
Iniparib
2006
SanofiAventis/
BiPar
Combination with gem carbo,
tmz
I.v.
Cancer
INO-1001
Inotek/ Genentech
Combination with temozolomide,
single
I.v.
Re-perfusion injury
Reformulation?
MK4827
(Niraparib)
2008
Merck/Tesaro
Single
Oral
Cancer
Phase III
(E7016, 2010)
(E7449, 2012)
GPI 21016
Eisai/
MGI Pharma
Combination with temozolomide
Oral
Cancer
Phase I
CEP-9722
2009
Cephalon
Combination with temozolomide
Oral
Cancer
Phase I
LT673 (BM673)
2011
Biomarin/LEAD
Therapeutics
Combination/single
Oral
Cancer
Phase III
JPI-289
2014
Jeil Pharmaceutical
Co
Single agent
Inflammation
Healthy volunteer dose finding
Phase III completed
2005/6
i.v
More recent drug development
timelines
Gandhi and Janne CCR 2012
Vemurafenib (PLX4032) entered phase I in 2008,completed phase III 2010 Licensed 2011
Mis-classification of iniparib has not helped
O’Shaughnessy et al SABCS 2009 poster 3122
 Iniparib is not a bone fide PARP inhibitor
 Non-selective modification of cysteine-containing proteins
 (Liu et al CCR 2012 18 510-523
 No selectivity for HRD cells, does not sensitise to top 1 inhibitors,
and no PARP inhibition in cell based assay
 (Patel et al CCR epub Jan 2012)
 But there are patient groups who benefit
Current status
 102 studies listed on www.clinicaltrials.gov
 31 actively recruiting patients
 5 agents in phase III studies
 ARIEL3 - rucaparib as switch maintenance in HGSO
 SOLO 1 and 2 Olaparib after platinum response in
BRCA ovarian cancer and as maintenance (2
studies)
 BRAVO – niraparib v physicians choice in BRCA
breast cancer
 BMN673 v physicians choice in BRCA breast cancer
 Brightness – veliparib + carbo v carbo added to
standard neo-adjuvant chemotherapy in TNBC
Dual Strategy for clinical development
PARP inhibitors potentiate radiotherapy and
DNA damaging chemotherapy
Temozolomide
Median RTV
Radiation
12
11
10
Median RTV
9
8
Control
7
699 10
6
TM 68
5
TM 68 + 699 0.1
4
TM 68 + 699 1.0
TM 68 + 699 10
3
2
1
0
0
10
20
30
40
Day
Irinotecan
50
60
70
Single agent activity - Synthetic Lethality
Spontaneous DNA damage
within cell:
20,000 SSB
10,000 depurinations
Why am I here?
BRCA
heterozygote cell
BRCA mutation -/-cell
BRCA -/cancer cells
BRCA +/normal cells
Adapted from Bryant et al. Nature 2005; 434:913-917
Single agent activity and dose response in
BRCA patients
400 mg BD
100 mg BD
Tutt et al The Lancet 2010 376(9737):235-44
EMA has accepted a Marketing Authorisation in BRCA
ovarian cancer based on sub-group analysis of Study 19
data
Fools rush in where angels fear to tread –
lessons from the past!
Alexander Pope
An Essay on Criticism 1709
The Bookful Blockhead, ignorantly read,
With Loads of Learned Lumber in his
Head,
With his own Tongue still edifies his
Ears,
And always List'ning to Himself appears.
Blocking direct repair to overcome
chemotherapy resistance
 Recommended dose for
combination 40 mg/m2
carmustine + 120 mg/m2
O6-benzylguanine
 Carmustine dose has to
be reduced to 20-25% of
single agent dose
Carmustine
O6benzylguanine
Schilsky et al, Clin Cancer Res 6:3025, 2000
PARPi chemo-potentiation studies – enhanced
myelosuppression is dose limiting
 Olaparib
 gemcitabine/cisplatin
 Paclitaxel
 DTIC
 Veliparib
 Topotecan
 Cyclophosphamide
 temozolomide
 Rucaparib
 temozolomide
 cis/pemetrexed
 carboplatin
Consequences of dual strategy (and too
many drugs?)
 Dose
 Single agent dose much greater than can be
safely given in combination
 Olaparib 300 mg BD continuously v 100mg bd
intermittently
 Rucaparib 600 mg bd continuously v 360 mg OD
intermittently in combination
 No focus on PD biomarkers and how much
enzyme inhibition is needed in each setting
Biomarkers
BRCA 1 and BRCA 2 germ line mutations
 Predominant registration strategy in metastatic
setting
 Can we safely use in adjuvant setting to avoid
surgery?
 hair follicle γH2AX biomarkers (Fong et al NEJM
2009)
 Myelodysplasia and pneumonnitis
 There is activity in non-BRCA related tumours
Gelmon et al Lancet Oncol 2011 12 852-861
 Ovarian cancer – BRCA-related and HGSO nonBRCA (confirmed in AZ Study 19)
 Continued debate in TNBC without a BRCAmutation
Biomarker development for HRD
 Primary cell culture for RAD51 foci formation after
DNA damage
 Gene expression profiling to identify a genetic
signature of HRD
 Multiple groups and companies investigating
 Markers of DNA damage and response in tumour
biopsies after treatment
 Nick Turners work in neoadjuvant breast cancer
demonstrating low RAD51 score after DNA damage as
predictor of HRD and sensitivity to chemotherapy
 CTCs in patients after treatment
 Shivaani Kummar and colleagues at NCI demonstrated
increased γH2AX foci after veliparib and topotecan
Functional biomarker assay for HRD
γH2AX/Rad 51 assay based on the principle of synthetic lethality
Co-localization of γH2AX and RAD51
foci in HR competent cultures
We need biomarker assay development
Ability to form RAD51 foci –
i.e repair DSB in primary ascites
cultures
Cytotoxicity to 10 µM AG014699 –
Synthetic lethality
Mukhopadhyay et al, CCR 2010
Are we going to sort out the problem child?
 PARPi likely to be used in combination even to exploit
HRD
 Single agent activity in HRD but not curative even in BRCAdefective background
 Scheduling
 to “avoid” the chemotherapy in HRD?
 Treatment breaks for normal tissue recovery with DNA damaging
agents
 Biomarkers – treat the right patients




BRCA1, BRCA2, PTEN loss
Functional HRD assay in sporadic cancers
Gene signatures and patient enrichment
Liquid assays – CTC and cfDNA
Acknowledgements
NICR team
Patients
Clinical research team
Hilary Calvert
Nicola Curtin
Herbie Newell
Roger Griffin
Chris Jones
Yvette Drew
Alan Boddy
Barbara Durkacz
Bernard Golding
Thank you for listening