Download Rucaparib (CO-338)

Rucaparib (CO-338)
April, 2015
Rucaparib: Summary
• Rucaparib is an oral, small molecule poly ADP-ribose polymerase (PARP)
inhibitor that is a potent inhibitor of PARP-1 and PARP-2
• Rucaparib is being developed for the treatment of patients with cancers predisposed to PARP inhibitor sensitivity
• Our initial focus is on tumors with defective DNA repair function (BRCA1/2
mutations and BRCA-like genomic alterations) in ovarian cancer
• Promising activity seen in ovarian cancer at RP2/3D of 600mg BID
– 70% ORR (RECIST & CA-125) in patients with BRCA1/2 mutated tumors 1
– 48% ORR (RECIST & CA-125) in patients with a HRD / BRCA-like signature1
• Rucaparib is well tolerated – no discontinuations due to adverse events (AEs) –
ARIEL2
• Several global Phase 2/3 trials:
– Study CO-338-010 – Phase 2 ovarian cancer, platinum sensitive, BRCA1/2 mutated,
treatment setting
– ARIEL2 – Phase 2 ovarian cancer, treatment setting
– ARIEL3 – Phase 3 ovarian cancer, platinum sensitive, maintenance setting
• Additional information: http://www.clovisoncology.com/products-companiondiagnostics/rucaparib/
2
1Swisher,
SGO 2015
Rucaparib: a potent PARP-1 and PARP-2 inhibitor
• Rucaparib (CO-338; formerly known as AG-014447 and PF-01367338)
• Potent inhibitor of PARP-1 (inhibition constant (Ki) 1.4 nM) and PARP-2 (0.17
nM)
• As a single agent, rucaparib is cytotoxic to cells with a breast cancer gene 1
(BRCA1) mutation, BRCA2 mutation, or epigenetically silenced BRCA1,
consistent with the concept of synthetic lethality
R u c a p a r i b c y t o t o x ic i t y in a n is o g e n i c
o v a r ia n c e ll lin e p a i r
Rucaparib
90
80
(m e a n  S E M )
% v ia b ilit y r e la t iv e t o c o n t r o l
100
70
1 5 - fo ld in c r e a s e
60
in s e n s itiv ity in B R C A 1
50
m u ta n t c e ll lin e
40
30
20
B R C A 1 w ild -ty p e
10
B R C A 1 m u ta n t
0
1
100
10000
[R u c a p a r ib ] lo g 1 0 nM
3
Company data
3
Rucaparib efficacy in BRCA-mutated xenograft models
• Rucaparib has anti-tumor efficacy in BRCA-mutated cell line or patientderived xenograft (PDX) models
– Significant responses observed in ovarian, breast and pancreatic models
• Dose (150 mg/kg BID PO) used in murine xenograft studies is below AUC24
exposure of human RP2/3D
R u c a p a r ib e f f i c a c y i n M D A - M B - 4 3 6
R u c a p a r ib e f f ic a c y in H B C x 1 7
(B R C A 2 m u ta n t) x e n o g ra ft m o d e l
(B R C A 2 m u ta n t) T N B C P D X M o d e l
2000
1200
T u m o r v o lu m e
800
3
600
400
3
(M e a n m m  S E M )
R u c a p a r ib 1 5 0 m g /k g B ID
1000
(m m )  SEM
M e a n tu m o r v o lu m e
V e h ic le
1500
1000
V e h ic le
R u c a p a r ib 1 5 0 m g /k g B ID
500
200
0
0
5
10
15
20
25
30
35
40
45
*
*
0
0
10
20
30
D a y s p o s t- tr e a tm e n t
D a y s p o s t- tre a tm e n t
D o s i n g p e r io d
D o s in g p e r io d
4
Company data
40
50
Additional genes beyond BRCA1/2 involved in homologous
recombination and repair can confer rucaparib sensitivity
• Employed siRNA knockdown of homologous recombination repair (HRR)
genes as a model of deleterious mutation in 4 ovarian cell lines
• Knockdown of 48% of HRR genes induces sensitivity to rucaparib
– Cell line context effects observed within 4 ovarian lines examined
Rucaparib IC50 Fold Change After siRNA Knockdown in OVCAR-3 Cell Line
Controls
High sensitivity
Intermediate sensitivity
Low sensitivity
55
IC50=half maximal inhibitory concentration. NT4 = transfection control
Swisher, ENA 2014
Rucaparib clinical development
• CO-338-010 is a Phase 1/2, open-label, study of monotherapy oral rucaparib
treatment for patients with solid tumors who progressed on prior treatment
(Phase 1 portion) and patients with platinum-sensitive, relapsed ovarian cancer
associated with a deleterious BRCA mutation (Phase 2 portion)
• CO-338-017 (ARIEL2) is a Phase 2 single-arm, study of monotherapy oral
rucaparib for treatment of relapsed, high-grade ovarian cancer
• CO-338-014 (ARIEL3) is a Phase 3, randomized, double-blind study of
monotherapy oral rucaparib versus placebo as switch maintenance treatment in
patients with platinum-sensitive, relapsed, high-grade ovarian cancer who
achieved a response to platinum-based chemotherapy
• RUBY: A single arm, open-label, Phase 2 study to assess the efficacy of
rucaparib in metastatic breast cancer patients with a BRCA-like genomic
signature
• CO-338-023 (RUCAPANC) is a Phase 2, single-arm, open-label study of
monotherapy oral rucaparib as treatment for patients with previously treated
locally advanced or metastatic pancreatic ductal adenocarcinoma and a known
deleterious BRCA mutation
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Collaboration with Foundation Medicine to Develop Companion
Diagnostic to determine BRCA mutations and a BRCA-like genomic
signature
• Rucaparib is being developed in parallel with a companion diagnostic
(CoDx) program
• Collaboration with Foundation Medicine (FM) for CoDx development
and commercialization
• Clovis and FM are developing a homologous recombination
deficiency (HRD) signature that will identify patients most likely to
respond to rucaparib
– HRD signature encompasses BRCA1/2 mutations and determination of
BRCA-like alterations by comprehensive genomic profiling
– HRD signature identifies patients with a defect in homologous
recombination independent of BRCA1/2 mutation
– HRD signature prospectively applied to ARIEL2 Part 2 and ARIEL3
studies
• HRD signature in ovarian cancer is the initial focus
– Expansion of HRD signature in additional cancer indications currently
on-going
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HRD causes genome-wide loss of heterozygosity (LOH) that can
be measured by comprehensive genomic profiling based on NGS
BRCAmut
Hypothesis 1:
Ovarian cancer patients
with high genomic LOH
suggesting BRCA-like
signature will respond
to PARPi
BRCAwt
Hypothesis 2:
Ovarian cancer patients
BRCAwt
Chromosome No.
mut=mutation; NGS=next-generation sequencing; wt=wild type.
8
Swisher, SGO 2015
who are “biomarker
negative” (ie, with low
genomic LOH) will not
respond to PARPi
Diagnostic development: cutoff defined for BRCA-like signature,
being tested and refined
TCGA and AOCS Overall Survival Data Used to Develop LOH Cutoff to Identify
High-Grade Ovarian Cancer Patient Tumors with BRCA-like Signature
100
0.25
0.20
0.15
0.10
High genomic LOH (n=97)
Low genomic LOH (n=212)
80
Optimal LOH cutoff
Overall Survival
(% probability)
Log-rank P Value
(high vs low LOH groups)
0.30
60
Log-rank: P=0.0047
Hazard ratio=0.62
40
Independent predictor
from BRCAmut status
20
0.05
0
0
Genomic LOH Cutoff
Median overall survival:
56.4 vs 38.2 months
0
25
50
75
100
125
Overall Survival (months)
Prospective testing of prespecified cutoff in ARIEL2 and ARIEL3
The Cancer Genome Atlas (TCGA) Research Network. Nature. 2011;474:609-615; Wang ZC et al; Australian Ovarian Cancer Study (AOCS).
Clin Cancer Res. 2012;18:5806-5815.
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Swisher, ENA 2014
Rucaparib has a favorable pharmacokinetic profile in
patients with low variability
geomean variability in range difference:
geomean variability in range difference:
Plasma Cmin at steady state (µM)
Plasma Cmin at steady state (µM)
21
21
2x
2x
4x
4x
5x
5x
2x
1x
2x
1x
• High fat breakfast did not cause
clinically meaningful changes of
rucaparib PK
18
18
15
15
• Time to maximum concentration:
2.5 - 4 hours
12
12
9
6
3
0
• Plasma half-life of 17 hours with
steady state achieved by Day 8
9
6
• Patients treated with ≥360 mg
BID achieved desirable trough
levels
3
0
• Dose proportional PK observed
up to 600 mg BID
240
360
480
600 840
240
360 tablet
480
600 840
tablet BID (mg)
Rucaparib
Rucaparib BID (mg)
10
Company data
• Carboplatin co-administration did
not alter rucaparib exposure in a
clinically meaningful manner
ARIEL2 goal: Assess rucaparib sensitivity in prospectively
defined sub-groups of ovarian cancer
Endpoints:
Key Eligibility
• High-grade serous or
endometrioid ovarian
cancer
• ≥1 prior platinum
chemotherapy (PART 1)
• ≥3 prior platinum
chemotherapy (PART 2)
• Measurable disease
600 mg BID
rucaparib
continuously until
progression by
RECIST
N ~ 480
• Adequate tumor tissue
• No prior PARPi
CA-125=cancer antigen 125 test; ORR=overall response rate; PFS=progression-free survival;
RECIST=Response Evaluation Criteria In Solid Tumors.
11
11
• PFS (RECIST) in:
– BRCA mutation
– BRCA-like
– Biomarker negative
•
ORR (RECIST & CA-125)
•
Safety
•
Pharmacokinetics
Rucaparib is well tolerated – no discontinuations due to
adverse events (AEs) – ARIEL2 data
Treatment-Related AEs in ≥15% of Patients (N=121*)
Nausea
Fatigue
ALT/AST Increased
Dysgeusia
Constipation
Anemia/Low Hgb
Decreased Appetite
Vomiting
Diarrhea
Grade 1
Grade 2
Grade 3
Grade 4
0
20
40
60
80
100
Worst Grade (NCI-CTCAE v4), %
* Data as of 02 Feb 2015 in patients enrolled by 15 Oct 2014
AE=adverse event; ALT=alanine transaminase; AST=aspartate transaminase; Hgb=hemoglobin;
NCI-CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events.
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Swisher, SGO 2015
In ARIEL2, rucaparib has demonstrated robust clinical activity in
BRCA mutant, platinum-sensitive ovarian cancer patients
– 70% ORR (RECIST & CA-125)
– 14/23 (61%) of patients
continuing on
treatment (+) as of Feb 2015
• Responses observed in germline
and somatic BRCAmut tumors
Best Response in Target Lesions
Change from Baseline (%)
• Robust clinical activity observed
in BRCAmut patients (n=23)
– 65% ORR (RECIST)
120
100
80
60
40
20
0
-20
-40
-60
-80
-100
Somatic BRCA mutation
Indeterminate
Germline BRCA mutation
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+=ongoing.
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Swisher, SGO 2015
In ARIEL2 differential rucaparib activity seen in patients
with/without BRCA-like signature
•
Clinical activity observed in
patients with BRCA-like signature
(n=25)
– 40% ORR (RECIST)
– 48% ORR (RECIST & CA-125)
– 9/25 (36%) of patients
continuing
on treatment (+) as of Feb 2015
Few responses observed in BRCAwt
patients without BRCA-like signature
(n=13)
– 8% ORR (RECIST)
– 8% ORR (RECIST & CA-125)
– 1/13 (8%) of patients continuing
on treatment (+) as of Feb 2015
120
100
80
60
40
20
0
-20
-40
-60
-80
-100
Change from
Baseline (%)
•
Best Response in Target Lesions
BRCAwt
BRCA-like
+
+
+
+
+
+
+
+
+
120
100
80
60
40
20
0
-20
-40
-60
-80
-100
Biomarker negative
+
+=ongoing.
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Swisher, SGO 2015
ARIEL Program Prospectively Validates Clinical Utility
of the HRD Test
ARIEL2 Part 1
Pre-specified
HRD test
• Efficacy (PFS) in pre-specified HRD
subgroups
• Optimize definition of
rucaparib-sensitive patients
ARIEL2 Part 2
• Treatment setting
• Efficacy (ORR) in prospectively defined
HRD subgroups
ARIEL3
• Maintenance setting
• Efficacy (PFS) in prospectively defined
HRD subgroups
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Lock down HRD test
Test all ARIEL2 Part 2 tumor
samples, classify HRD status
Final
Analysis
Test all ARIEL3 tumor samples,
classify HRD status
Final
Analysis
Rucaparib: Differentiation and areas of interest
• Rucaparib has a unique efficacy profile and biomarker strategy:
– 70% ORR (RECIST & CA-125) in OC patients with BRCA1/2 mutated
tumors1
– 48% ORR (RECIST & CA-125) in OC patients with BRCA-like tumors1
– Companion diagnostic developed for determining BRCA-like genomic
signature in addition to BRCA mutations; prospectively applying this
analysis in ARIEL2 Part 2 and ARIEL3 studies
• Clovis is interested in expanding rucaparib monotherapy efficacy
studies and predictive HRD / BRCA-like signature development in
additional cancer indications beyond ovarian including breast,
prostate, gastroesophageal, endometrial and lung cancer
• Clovis is interested in performing drug combination studies with
rucaparib including targeted therapies (e.g. CDKi, PI3Ki, HSP90i,
HDACi, CHKi), immunotherapeutics (e.g. PD-1, PD-L1 mAb),
anti-angiogenics (small and large molecule) and radiotherapy
16
1Swisher,
SGO 2015