Transcript Marketing Excellence Project 2nd Steering Committee Meeting

1
The nab-Paclitaxel Difference
2
The nab-Paclitaxel Difference
•
•
•
•
•
•
Technology
MoA
Tumor uptake
Selectivity for tumor vs healthy tissue
Efficacy
Safety
3
nab-Paclitaxel is The First Tumor-Targeted Nanomedicine
to Leverage the Natural Transport Properties of Albumin
nab-Paclitaxel
individual molecule
nab-Paclitaxel
complex
4–14 nm in size3,4
Albumin
Paclitaxel
130 nm in size1,2
• A single molecule of albumin can bind up to 6 or 7 molecules of paclitaxel5
1. Desai et al. SABCS. 2004 [Abstract 1071].
2. Kratz et al. J Control Release. 2008;132(3):171-183.
3. Peters, Jr. Adv Protein Chem. 1985;37:161-245.
4. Desai. Drug Delivery Report. 2008;Winter 2007/2008(16):35-41.
5. Paal et al. Eur J Biochem. 2001;268:2187-2191.
4
The MOA of nab-Paclitaxel Differs From That of
Conventional Paclitaxel1-5
In
Preclinical
Unlike
vitro conventional
datadata
thatthat
transcytosis
binding
Cremophor
paclitaxel,
nab-paclitaxel
to endothelial
EL
ofavailability
nab-paclitaxel
at physiological
accumulation
cells
ofisactive
9.9-fold
islevels
over
in drug
tumors
5nab-paclitaxel
55 5
1-4
4-fold
higher
blocks
is 33%
not
limited
higher
the
for
higher
nab-paclitaxel
binding
by entrapment
than
thanof
that
that
paclitaxel
ofofvs
in
conventional
conventional
conventional
micelles
to albumin
with
paclitaxel
paclitaxel
paclitaxel
Endothelial
cells
nab-Paclitaxel
Dissolution
Binding
Transcytosis
Tumor uptake
Conventional
Paclitaxel
Albumin
Paclitaxel
Albumin receptor
SPARC and other extracellular matrix albumin-binding proteins
Tumor cells
Cremophor solvent micelles
Investigation of the functional importance of SPARC with respect to nab-paclitaxel is ongoing.
MoA, mechanism of action; SPARC, Secreted Protein Acidic and Rich in Cysteine.
References in slide notes.
5
At the Same Dose and Same Duration,
Tumor Uptake is 33% Higher for nab-Paclitaxel1
8
Concentration
(µg paclitaxel/g)
7
6
nab-Paclitaxel
Conv Paclitaxel
5
4
Tumor AUC nab-Paclitaxel =
1.33 × Conv Paclitaxel
P < .0001 ANOVA
3
2
0.01
0.1
1
10
100
Hours
• Dose of both nab-paclitaxel and conventional paclitaxel = 20 mg/kg dose of paclitaxel; experiments in
human breast tumor xenografts in nude mice.
ANOVA, analysis of variance; AUC, area under the curve;
conv, conventional.
1. Desai et al. Clin Cancer Res. 2006;12:1317-1324.
6
nab-Paclitaxel Demonstrates Greater Tumor
Selectivity1,2
Relative concentration
(nab-Paclitaxel/Conventional paclitaxel)
• nab-Paclitaxel demonstrates greater tumor selectivity compared with
conventional paclitaxel in this preclinical model1,2
1.5
1.0
nab-Paclitaxel
>
Conv paclitaxel
nab-Paclitaxel
=
Conv paclitaxel
nab-Paclitaxel
<
Conv paclitaxel
0.5
0
• Comparative tissue distribution (ratio) of radiolabeled drug in mice
bearing human breast tumor xenografts 1 hour after dose 1,2
conv, conventional.
1. Hawkins et al. AACR. 2003. Poster 1189.
2. Scheff . Community Oncol. 2008;5(7 suppl 8):7-13.
7
nab-Paclitaxel Clinical Data
Approved indication in the EU (SmPC):
Treatment of metastatic breast cancer in adult patients
who have failed first-line treatment for metastatic
disease and for whom standard, anthracycline
containing therapy is not indicated
8
Overall Survival is Increased With nab-Paclitaxel1,3
OS Results in MBC from CA 024 (Phase II) & CA 012 (Phase III)
CA 024,1,2 Phase II, first-line mBCa,b
CA 012,3,4 Phase III, > first-line MBC
nab-Paclitaxel 260 mg/m2 q3w (n = 131)
Conventional paclitaxel 175 mg/m2 q3w (n = 136)
nab-Paclitaxel 150 mg/m2 qw 3/4 (n = 74)
Docetaxel 100 mg/m2 q3w (n = 74)
0.75
26.6
0.50
0.25
33.8
+7.2
0
1.00
Probability of Survival
Probability of Survival
1.00
0.75
13.0
10.7
0.50
+2.3
0.25
0
0
10
20
30
40
Months
HR = 0.688,1 P = NS
anab-Paclitaxel
0
10
20
30
Months
HR = 0.726,5 P = 0.0204
300 mg/m2 q3w and 100 mg/m2 qw 3/4 arms not
shown.
bOS calculated when 58% of patients had died.
HR, hazard ratio; NS, not statistically significant;
OS, overall survival; q3w, every 3 weeks; qw 3/4, first 3 of 4 weeks.
1. Gradishar et al. ASCO Breast Cancer Symposium. 2011 [Abstract 275].
2. Gradishar et al. J Clin Oncol. 2009;27(22):3611-3619.
3. Gradishar et al. J Clin Oncol. 2005;23:7794-7803.
4. Abraxane® European SmPC; log-rank test.
5. Celgene Corporation; Data on file.
9
nab-Paclitaxel Demonstrates Antitumor Activity
Where Conventional Taxanes have Failed1-4
• In patients with MBC
– Phase II study:1,2 patients with prior taxane exposure had a 43% response
rate to nab-paclitaxel
– Phase II study:3 nab-paclitaxel showed efficacy (ORR 14–16%,
DCR 26–37%) and was well-tolerated in taxane refractory patients
• Phase I study: 4 photographs illustrating reduction of breast lesions in a
62-year-old NSCLC patient following treatment with nab-paclitaxel
Patient did not respond
to conventional paclitaxel
DCR, disease control rate; NSCLC, non-small cell lung cancer;
ORR, overall response rate.
Following nab-paclitaxel treatment
1. Ibrahim et al. J Clin Oncol. 2005;23:6019-6026.
2. Ibrahim et al. ASCO 2002 [Abstract 209].
3. Blum et al. Clin Breast Cancer. 2007;7(11):850-856.
4. Campbell et al. ASCO 2002 [Abstract 403].
10
nab-Paclitaxel has a Different Tolerability Profile vs
Conventional Paclitaxel in Patients with MBC1-4
CA 012 Phase III Trial
Selected adverse events, %
nab-Paclitaxel
260 mg/m2 q3w
(n = 226)
Grade 3
Grade 4
Conv paclitaxel
175 mg/m2 q3w
(n = 222)
Grade 3
Grade 4
P-value
Hematologic
Neutropenia
Thrombocytopenia
Anemia
Febrile neutropenia
Non-hematologic
Sensory neuropathy
Fatigue
Myalgia
Vomiting
Edema
Hypersensitivity
Median time to improvement of SN
to grade ≤ 2 (days)
Table adapted from Davidson 20101
conv, conventional; NS, not statistically significant;
SN, sensory neuropathy.
25
<1
<1
<1
9
0
<1
<1
32
<1
0
<1
22
0
<1
0
< .001
NS
NS
NS
10
8
7
3
0
0
0
<1
0
<1
0
0
2
3
2
1
<1
1
0
<1
0
0
0
0
< .001
NS
NS
.002
NS
NS
223
793
.0284
1. Davidson. EJC Supplements. 2010;8(1):11-18.
2. Gradishar et al. J Clin Oncol. 2005;23(31):7794-7803.
3. Cortes et al. EJC Supplements. 2010;8(1):1-10.
4. Celgene Corporation. Data on file [CA 012 CSR].
11
nab-Paclitaxel is different from
conventional paclitaxel because …
…it leverages albumin to target1 and
delivers more drug to the tumor,2
resulting in higher ORR and OS3
ORR, overall response rate; OS, overall survival.
1. Lammers et al. Br J Cancer. 2008:99;392-397.
2. Desai et al. Clin Cancer Res. 2006;12:1317-1324.
3. Gradishar et al. J Clin Oncol. 2005;23(31): 7794-7803.
12
BACK-UPS
13
Overall Survival is Increased With nab-Paclitaxel1
CA 024 Randomized Phase II Trial, First-Line MBC Patients Receiving
nab-Paclitaxel qw 3/4 at 150 mg/m2 or Standard Docetaxela,b
1.00
nab-Paclitaxel 150 mg/m2 qw 3/4 (n = 74)
Probability of Survival
Docetaxel 100 mg/m2 q3w (n = 74)
0.75
26.6
33.8
HR = 0.688
0.50
0.25
+7.2
0
0
10
20
30
40
50
Months
•
The 150 mg/m2 qw nab-paclitaxel arm demonstrated a numerically longer OS
versus docetaxel (not statistically significant)
anab-Paclitaxel
300 mg/m2 q3w and 100 mg/m2 qw 3/4 arms not shown.
calculated when 58% of patients had died.
HR, hazard ratio; OS, overall survival; qw, weekly; q3w first 3 of 4 weeks.
bOS
1. Gradishar et al. ASCO Breast Cancer Symposium. 2011 [Abstract 275].
2. Gradishar et al. J Clin Oncol. 2009;27(22):3611-3619.
14
Overall Survival is Longer With nab-Paclitaxel1
CA 012 Randomized Phase III Trial, > First-Line MBC Patients Receiving
nab-Paclitaxel or Conventional Paclitaxel
1.00
nab-Paclitaxel 260 mg/m2 q3w (n = 131)
Probability of Survival
Conventional paclitaxel 175 mg/m2 q3w (n = 136)
0.75
13.0
10.7
0.50
HR = 0.73, P = 0.024
+2.3
0.25
0
0
10
20
30
Months
HR, hazard ratio; OS, overall survival; q3w, every 3 weeks; qw 3/4, first 3 of 4 weeks.
1. Gradishar et al. J Clin Oncol. 2005;23:7794-7803.
15
nab-Paclitaxel is different from
conventional paclitaxel because …
…it leverages albumin to target1 and
delivers more drug to the tumor,2
allowing for greater clinical efficacy3
…it targets tumors,4 achieves higher
tumor uptake,2 and produces superior
clinical efficacy3
ORR, overall response rate; OS, overall survival.
1. Lammers et al. Br J Cancer. 2008:99;392-397.
2. Desai et al. Clin Cancer Res. 2006;12:1317-1324.
3. Gradishar et al. J Clin Oncol. 2005;23(31): 7794-7803.
4. Scheff . Community Oncol. 2008;5(7 suppl 8):7-13.