FDA_LYNPARZA Olaparib.pptx

MASTER 2 AREIPS
February 2015
Lantier.L; Gillet.D; Marquegnies.V, Despres.C; Cumzain.M;
Caminade.C; Gouy.C; Khamassi.H; Roye.C; Courvoisier.B;
Tournoys.L; Jeannot.A; Hologne.P; Roselmac.C; Renaux.V
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9.
Introduction
Regulatory procedures
Pharmacology
Toxicology
CMC
Clinical Trials
Medical Device
Name Review
Post Marketing Studies
2
Introduction
3



December 19, 2014 approved
by FDA
Monotherapy for the
treatment of patients with
deleterious or suspected
deleterious germline BRCA
mutated (gBRCAm)
detected by an FDA-approved
test : BRACAnalysis CDx
(Myriad Genetics) for the
qualitative detection and
classification of variants in
the BRCA1 and BRCA2 genes.
4
5th cause of cancer
Population estimated :
22 000 new cases diagnosed
14 270 deaths
in the US in 2014
http://www.ovariancancermd.com/staging/
http://www.cdc.gov/cancer/ovarian/statistics/
5
http://www.ovariancancermd.com/prognosis/
6

BRCA1 and BRCA2, encode proteins involved in
the DNA damage repair pathway.

Deleterious mutations are :

↗ incidence several cancers (ovarian, breast…)

Ovarian and breast cancer characterized by :
• autosomal dominant pattern
• The Majority are protein truncating → loss of function
• 10-40% lifetime risk of developing ovarian
cancer
• 50-85% for breast cancer
 earlier age
 bilateral
7

gBRCAm = 10-15% of ovarian cancer
◦ 2 000 cases per year in the U.S.
8
Debulking
surgery
Chemotherapeutic
regimens:
• platinum agent
(carboplatin or
cisplatin)
•taxane (paclitaxel
or docetaxel)
Targeted therapy:
 Olaparib
9

Olaparib 50 mg capsules (Lynparza®) :
◦ Monotherapy for the treatment of patients with
deleterious or suspected deleterious germline BRCA
mutated (gBRCAm)
◦ advanced ovarian cancer who have been treated
with three or more prior lines of chemotherapy.

Posology : 400 mg (8 capsules) 2/ day.
10


Inhibitor of poly (ADP-ribose) polymerase
(PARP) enzymes.
Including PARP-1, PARP-2, and PARP-3.
11


PARP 1, 2 and 3  DNA-dependent enzymes
that are catalytically activated upon binding
to DNA damage.
Inhibition  DNA damaged accumulation and
cell death.
Source : http://www.onclive.com/publications/Oncology-live/2013/August-2013/New-Life-for-PARPInhibitors-Emerging-Agents-Leave-Mark-at-ASCO
12
(HR)
http://www.nature.com/nrclinonc/journal/v12/n1/full/nrclinonc.2014.163.html
13
Olaparib
(HR)
http://www.nature.com/nrclinonc/journal/v12/n1/full/nrclinonc.2014.163.html
14

BRACAnalysis CDx™ developped in parallel to
detect variant in BRCA 1 et BRCA 2 genes to select
patients for an Olaparib treatment.
Regulatory
procedures
17
Orphan drug
status granted
IND 75918
activated
August
2006
Pre-submission
meeting
October
2012
Guidance
meeting
March
2013
Breakthrough
therapy request
Pre-NDA
meeting
October
2013
Approval
Oncologic Drug Advisory
comittee
February
2014
NDA 206162
submitted
June
2014
July
2014
December
2014
Major
admendment
18
Companion diagnostic development
Class 3
PMA
CDRH Center for Device and Radiological Health
Priority review:
15 oct 2014
Orphan statut:
16 oct 2013
Oncologic Drug advisory
committee
Drug develop
Approval: 19
dec 2014
Priority review:
April 2014
Accelerated
approval & NDA :
19 dec 2014
19
Pharmacology
23

Goal :
evaluate the PARP inhibitory activity of olaparib in
SW620 human colon adenocarcinoma cell line

How ?
◦ SW620 extracts (lysates) were incubated with 0 – 300 nM
olaparib for 5 minutes at 30°C in the presence of
deoxyribonucleic acid
◦ Immunoassay detecting formation of poly ADP-ribose
(PAR), a downstream product of PARP activation
24
Immunoassay detecting formation of poly ADP-ribose (PAR), a downstream
product of PARP activation
PARP
PAR
poly ADP-ribose
25
Results :

IC50 = 5,48 nM
IC90 = 60,08 nM
Conclusion :
Olaparib inhibited formation of PAR in SW620 extracts in a dosedependent manner.

26

Goal :
Evaluate the effect of Olaparib on
cell viability in a panel of 95 cells
lines of colorectal, breast,
ovarian, pancreatic, head and
neck squamous cell carcinoma,
and non-small cell lung cancer
origin

How ?
CFA (Colony Forming Assay)
Gold standard for measuring the
effects of cytotoxic agents on
cancer cells in vitro
27

Results :
28

Conclusion :
In vitro, treatment with olaparib resulted in
decreased cell viability, as measured by the
colony formation assay, in cell lines from breast,
ovarian, pancreatic, non-small cell lung, and
colorectal cancers, and head and neck small-cell
carcinoma
29

Goal :
Evaluate whether cell lines and tumors which were
sensitive to platinum based chemotherapies were
also sensitive to olaparib

How ?
Anti-tumor activity was evaluated in patient derived
mouse tumor models of triple negative breast cancer
(any breast cancer that does not express the genes for Estrogen
Receptor, Progesteron Receptor and Her2/neu) :
Measure of tumoral volume of HBCx-10
(mutated BRCA2 and sensitive to cisplatin)
cells
30

Results :
31

Conclusion :
- In vivo, olaparib showed anti-tumor activity in
breast patient-derived tumor models which were
also sensitive to cisplatin treatment.
- Co-treatment with olaparib and cisplatin resulted
in greater anti-tumor effects when compared to
either agent alone.
32
Goal :
Evaluate the growth inhibitory activity of
olaparib in a panel of 95 cancer cell lines :
colorectal, breast, ovarian, pancreatic…

How ?
Colony Forming Assay

33

Results :
HRR : homologous
recombinant repair
34

Results :
35

Conclusion :
Cell lines with BRCA1/2 mutations or low expression
of
homologous
recombination
repair
(HRR)
genes/proteins were more sensitive (IC50 < 1 µM) to
growth inhibitory activity by olaparib
36
Pharmacokinetic
 A  Rats, Mouse, Dogs: Cmax and biodisponibility more
important F/M.
 D  Rats, Mouse, Dogs, Human : no distribution in a
particular organ & no differences between male and
female.
 M  Rats & Dogs 3 major metabolites, no unique
human metabolite present at disproportionately higher
levels in human than the rat identified.
E
 Rats Approximately 92% of the dosed radioactivity
was excreted 24h post-dosing & Radioactivity was
excreted predominantly in the feces.
 What’s about the human excretion?
38
Toxicology
50
Toxicity 28 days in RATS


Tested doses
0
5 mg/kg
15 mg/kg
40 mg/kg
Control
Active dose
No adverse effect
Dose expected in humans
~ 2 to 18% of human AUC
MTD in rats
Dose ≥ 100 mg/kg/day
◦ Hematological toxicities REVERSIBLE following a 21-day non-dosing period

No apparent accumulation with repeated dose of
olaparib
51
Toxicity 28 days in rats
40 mg/kg
Clinical signs
Salivation, paddling
↘ body weight in males (normal: end of recovery)
FEMALES
Hematological
modifications
Myelogram
Histological lesions
Pharmacocinetic
Urinary effects
Regenerative anemia (↘ red cells, Hb / ↗ reticulocytes, MCV )
 Visible bone marrow /splenic hematopoiesis
•
• ↗platelet
• ↘ white cells, lymphocytes
End of recovery: leukocytes and lymphocytes slightly ↘.
•
•
↗ erythroid cells
↘ myelopoietic cells (female ++)
during study
Hemosiderin in hepatocytes (hemorrhage, ↘ red cells)
↗ X 3-8 Cmax and AUC values in females
↗ 40-50% urinary volume
52
Toxicity 26 weeks in RATS
 DOSES
•
•
Males: 0; 5 mg/kg; 15 mg/kg ;30 mg/kg
Females: 0; 1 mg/kg ;5 mg/kg ;15 mg/kg
 Systemic exposure significantly higher in female rats
≥ 15 mg/kg
FEMALE
Clinical signs
↘ body weight,
Dose dependent
Hematological
modifications
↗ late myeloid cells
↗ M/E
53
Toxicity 28 days in DOGS
DOSES:
• 0 ; 2,5 ; 5; 15 mg/kg
• 30 mg/kg: MTD in dos, significant hematological studies
Lesions
≥ 2.5 mg/kg
↘ reticulocytes, platelets, leukocytes, lymphocytes
Dose-dependent
Bone marrow atrophy
Delay in erythroid cells
 NO MORE DIFFERENCES AFTER RECOVERY PERIOD
Minimal or slight microscopic findings
≥ 5 mg/kg
Spleen
GI tracts (congestion , hemorrhage), pancreas (pale)
Urinary bladder (congestion, hemorrhage), parathyroid,kidney
Prostate (inflammation)
 ORGAN LESIONS: PERSISTENCE AFTER RECOVERY PERIOD
15 mg/kg
Cmax and AUC values : X 2 in female dogs
54
Toxicity 26 weeks in DOGS
Results
≥ 3 mg/kg
↘ red cell mass,
↘ reticulocytes, platelets, leukocytes (all lines)
Lack of regenerative response in bone marrow
Inflammation: stomach, prostate
10 mg/kg
Male dogs
↗ M/E ratio,
↗ myeloid cells
↘ erythroid cells
Female dogs
↘ M/E ratio
↘ myeloid cells
↗ erythroid cells
WEIGHT VARIATIONS:
• Male dogs : ↗ ~30% at the 1 and 3 mg/kg
• Female dogs: ↗ ~70% at 10 mg/kg
Without change in food consumption
End of study: no microscopic correlates in the bone marrow or lymphoid organs
55

Ames test: negative
◦ Not mutagenic at concentrations up to 5000 μg/plate under the
conditions tested

Cytogenetic analysis on Chinese Hamster ovarian cells
◦ Olaparid is clastogenic
◦ Dose dependent effect

Micronucleus test (in vivo)
◦ Doses: 100; 200; 400 mg/kg
◦ Bone marrow toxicity all doses: clastogenic
56

NO STUDY
« Consistent with recommendations in ICH S9, these studies are not
essential to support an NDA for the proposed patient population. »
57
Fertility and early embryonic development

FEMALE RATS

Doses: 0; 0,05 (NOEL); 0,5 ; 15 mg/kg
Modifications
15 mg/kg
( ~11% of human AUC)
After 15 mg/kg
+ 4 weeks recovery
•
•
•
•
Minimal maternal toxicity :↓ ~ 5% body weight
↗ pre-implantation loss
↗ early intrauterine deaths
↗ post-implantation loss
No effects on mating, fertility, or embryo-fetal survival.
58
Fertility and early embryonic development


MALE RATS
Doses: 0; 5; 15 ; 40 mg/kg
Modifications
40 mg/kg
≤40 mg/kg
+ 4 weeks recovery
(7% of human AUC)
•
•
•
↘ or ↗ body weight
Salivation
Hair loss
No effects on mating and fertility rates
compared to controls
59
Embryonic fetal development
Dose
Effect
≥ 5 mg/kg/day
(2% of human AUC)
EMBRYOTOXIC
 no viable offspring
Major fetal malformations
During organogenesis
0.05 and 0.5 mg/kg
(≤ 0.3% of human AUC)
•
•
Eye , anophthalmia, microphthalmia
Vertebra/ribs, limbs, skull,diaphragm:
ossification disorders
Minor malformations:
•
•
Skeletal
Visceral abnormalities (kinked, dilated
ureter, additional liver lobe…)
60
Chemistry
Manufacturing
Control
61
Olaparib
Formule
C24 H23FN4O3
Chemical
name
4-[(3-{[4- (cyclopropylcarbonyl)
piperazin-1-yl]carbonyl}-4fluorophenyl)methyl]phthalazin1(2H) one
Molecular
weight
434.46 g/mol
Appearance
White, crystalline solid
Solubility
Low solubility, pH-independent
characters
Not hygroscopic, Non-chiral center
Free base,
BCS
Class 4 (low solubility, low
permeability)
ICH S2
classified as genotoxic
62


Manufacturing site and analysis
for release:
Patheon Pharmaceuticals Inc.
Cincinnati, OH 45237
Packaging : AstraZeneca
Pharmaceuticals LP USA
63
Presentation
Olaparib 50 mg capsules
Excipient
lauroyl polyoxylglycerides
Hard Capsules
are white, opaque, composed of
hypromellose, titanium dioxide, gellan gum,
potassium acetate
Capsule printing
ink
shellac, ferrosoferric oxide
Mark
“OLAPARIB 50 mg” and the AstraZeneca
logo printed in black ink
64
Test procedure Drug substance
Test procedure Drug product
Description
Description
identification
identification
Assay
Assay
Organic impurities
Degradation product
any individual unspecified
largest individual unspecified
Total
Total
Particule size
Dissolution
Residual solvents
Uniformity of dosage units
65

FDA demand:
 Change of maximal content of degradant
 Addition of a release test

Stability:
◦ Appearance testing: thermal failure for several batches
 capsule leakage and printing ink smudged

Consequences
◦ Post Marketing commitment: conduct stability study of
commercial product : minimum of 3 batches

Shelf-life: 18 months
66

Storage condition : 20°C
to 25°C
Excursion permitted :
15°C to 30°C
should not be exposed:
>40ºC
Container closure system:
Bottle of HDPE with cap and seal
aluminium foil
112 capsules per bottle
4 bottles per carton
67
Clinical Trials
68
Trial 19:
 Indication: Maintenance treatment in patients
with platinum sensitive relapsed ovarian
cancer with germline BRCA mutation who are
in response to platinum based chemotherapy
 Accelerated Approval?
 25/06/2014: meeting of the committee
◦ 11 answered NO
◦ 2 answered YES


New indication: use data trial 42
+ supportive trials (2, 9, 12, 20, 24)
69








Single, open-label, non-randomized trial
Phase II
Non-comparative, multicenter
Aim: to assess efficacy and safety of olaparib
(400 mg x2/day)
Patients with advanced cancers who have a
confirmed genetic BRCA1/2 mutation
N=317 patients
94% caucasian
Median age : 58 years old
70

≥ 18 years of age

Confirmed documented deleterious or suspected
deleterious BRCA mutation



Histologically or, cytologically confirmed malignant
solid tumor refractory to standard therapy and for
which no suitable effective standard therapy exists
For the ovarian cancer : progressive or recurrent disease
according to RECIST 1.1
The analysis of all primary and secondary objectives
occurred 6 months after the last patient has
commenced study treatment
71
19 patients excluded
No treatment
317 patients
all cancer
298 patients
received the
treatment
105 patients
with others
cancers
193 patients had an
ovarian cancer
56 patients
with less than 3
chemotherapy
137 patients treated
with 3 or more
chemotherapy
72
D-28 :
DO :
Baseline radiological
tumor assessment
Start of the
treatment
Every 8 weeks :
Assessment of the
tumor
Stop treatment when there is a disease progression or intolerance
73
Primary
endpoints
Secondary
endpoints
CR
ORR
Complete
response
Objective
response rate
PR
PFS
Partial
response
Progression
free survival
OS
Overall survival
DOR
Duration of
response
DCS
Disease control
rate
74


Many investigators, cooperative groups, industry
and government authorities have adopted these
criteria in the assessment of treatment outcomes
Tumour lesions/lymph nodes
◦ Measurable
◦ Non-measurable

Target lesions : into measurable lesions
◦ Maximum 5 lesions, maximum 2 per organ

Non target lesions : all the other lesions
75

Complete response : CR
◦ Disappearance of all target
lesions
◦ Reduction of any
pathological lymph nodes
(<10 mm)
◦ Disappearance of all nontarget lesions and
normalisation of tumour
marker level

Partial response : PR
◦ 30% decrease in the
sum of diameters of
target lesions
76
77
78
Design
Objectives of Study
Endpoint
gBRCAm
(n)
≥3 lines
chemotherapy
Study 2
Phase I
Expansion cohort
Safety
tolerability
ORR
5
3
Study 9
Phase II
Single Arm Study,
multicenter, noncomparative
Assess efficacy of 2
dose levels
ORR
33
26
Study 12
Phase II
Randomized
Open-label
Compare efficacy of 2
dosage
PFS
32
16
Study 20
Phase II
Single arm study
Non-comparative
Determine response
rate and correlative
markers of repsonse
ORR
17
12
Study 24
Phase I
Randomized
Bioavailability for
different FP
ORR
20
11
79

205 patients: 137 from Trial 42 and 68 from
5 supportive trials
80

Most common
adverse reactions :
◦
◦
◦
◦
◦
◦
◦
◦
◦
Anemia
Nausea
Fatigue (asthenia)
Vomiting
diarrhea
dysgeusia
dyspepsia
headache
decreased appetite
◦ nasopharyngitis/phary
ngitis/URI
◦ Cough
◦ arthralgia/musculoske
letal pain
◦ myalgia
◦ back pain
◦ dermatitis/rash
◦ abdominal
pain/discomfort
◦ Perturbation of NFS
81

Including in warning and precautions :
◦ Myelodysplastic syndrome/Acute Myeloid Leukemia
(2%)
◦ Pneumonitis (<1% )
◦ Embryo-fetal toxicity
82
Data available from 13 phase 1 & 2 trials.

No food effect

Eliminaton by metabolism (CYP3A4) +++

Elimination by Renal route +
◦ No dose adjustement for IR but monitoring

Mean-half time: 12 hours at the 400 mg dose

Plasma protein binding of 89%

Drug interaction with CYP3A4:
Inhibitor
Inducer
Itraconazole
 [olaparib]
Rifampicin
 [olaparib]
Fluconazole
 [olaparib]
Efavirenz
 [olaparib]
83
84
Parameters after Single Dose Olaparib in Trial 24
85
Medical
Device
86

In vitro diagnostic device intended for the qualitative
detection and classification of variants of the BRCA1
and BRCA2 genes using genomic DNA obtained from
whole blood specimens collected in EDTA

2 methods of DNA sequencing:
◦ BRACAnalysis CDx Sanger sequencing: senquencing and
PCR to detect single nucleotide variants and small
insertions and deletions
◦ BRACAnalysis CDx Large Rearrangement Test (BART® CDx):
multiplex PCR detects large daletions and duplications
87

Samples from:
◦ Ovarian cancer patients
◦ Breast cancer patients
◦ People from families with or without a high risk for
hereditary breast an ovarian cancer

Samples selected to represent a range of
variants detected by the device
89

Sanger sequencing: comparison with a validated
next-generation sequencing
◦ 100 samples
◦ Overall agreement = 100%

BART®: comparison to a validated microarraybased test
◦ 100 samples
◦ Overall agreement = 94% (95% CI: 87.4%-97.8%)
 Good accuracy of BRACAnalysis CDx
90

Sanger sequencing
◦ 5 samples to evaluate 6 DNA input concentrations
◦ Protocol: Optimal DNA input concentration: 20 ng
◦ Tolerance range from 1 ng to 100 ng

BART®
◦ Protocol: optimal concentration of 8 ng
◦ DNA input levels from 2 ng to 12 ng generate
similar results than with 8 ng
 Good sensitivity
91

Sanger sequencing:
◦ In silico analysis
◦ No non-specific sequence were predicted for any
primer pair combinations

BART® test:
◦ Bioinformatic program
◦ Non-specific products were not predicted for any of
the primer pairs
 Highly specific
92

Assessment of interfering effects of :
◦ Endogenous substances in human: Hemoglobin,
Albumin, IgG, Bilirubin
◦ Exogenous substance: K3EDTA
◦ Substance used in standard process of the device:
ethanol bleach

Interfering substances did not affect the
performance of tests, except IgG at 60 g/L

At 9,5 g/L of IgG, the acceptance criterial
were met
93

Reproductibility: Test of 20 samples over 3
independant runs
◦ Overall agreement = 100%

Repeatability: reproductible results across
replicates of the same sample
◦ Sanger sequencing:
 one batch = 100% concordant results,
 an other 8 of 9 reactions were concordant
◦ BART®test: concordant results
 Good reproductibility and repeatability
94


To evaluate if the performance of the tests is robust
to withstand process variations
Sanger sequencing:
◦ PCR annealing temperature: +/- 1, 2, 3°C: positive for all T°
◦ Sequencing annealing temperature: +/- 1, 2, 3°C: positive
for all T°

Robustness of BART®:
-3° -2° -1° 0
+1° +2°C +3°C
◦ PCR annealing temperature:
◦ Injection time:
 all conditions were concordant: except 20s
 Optimal: 6s, acceptable range from 2 to 10s
Miscalled
deletion
results
95

DNA extraction
◦ No cross contamination were detected during
extraction

BART®test
◦ 10 samples
◦ Callable results and concordant with the expected
results
96

Blood specimen:
◦ Blood samples stored at 2 different temperatures:
4°C (standard)
14, 30, 37 days
30°C
3, 5 and 7 days
30 days at 4°C and
5 days at 30°C


Reagent stability: different reagents used in assays,
stored under different temperatures and tested at
defined time points
Intermediate product stability
97

High specificity for all targeted regions in the
BRCA1 and BRCA2 genes

Good accuracy, sensitivity and specificity
However, a limited range of variant types was
included in some of the studies
 CDRH request additional testing

98
●
●
BRACAnalysis Cdx = in vitro medical device for the
detection of gBRCAm
The aim of BRACAnalysis clinical studies is to
compare the results obtained with
● « local test »
● BRACAnalysis Cdx
For a positive approval :
BRACAnalysis Cdx results ≥ local test results
●
10
0

Retrospective study

Non randomized

Objective:
◦ To demonstrate clinical utility of BRACAnalysis CDx
◦ To analyse efficacy and safety data obtained with
BRACAnalysis CDx to assess efficacy and safety olaparib

Endpoints:
◦ Subjects with response
◦ Objective response rate
◦ Duration of response
10
1
Design
317 patients
Advanced cancer
193 patients with
ovarian cancer and
gBRCAm +
61 patients available for
Retrospective testing with
BRACAnalysis CDx
-2 false
positives
137 patients had
received 3 lines of
chemotherapy
Tested with local test
59 patients with
confimed gBRCAm
with BRACAnalysis
CDx
78 patients tested
with local test
(samples not available)
10
2
137 patients had
received 3 lines of
chemotherapy tested
with local test
59 patients with
confimed gBRCAm
with BRACAnalysis
CDx
•
•
•
•
•
•
Subjects with response : 33.6%
ORR: 0.34 (0.26-0.42)
DoR: 7.9 (5.6 - 9.6)
78 patients tested
with local test
(samples not
available)
Subjects with response: 40.7%
ORR: 0.41 (0.28-0.54)
DoR: 8.0 (3.8 - NC)
10
3
59 patients with
confimed gBRCAm
with BRACAnalysis
CDx
•
•
•
Subjects with response: 40.7%
ORR: 0.41 (0.28-0.54)
DoR: 8.0 (3.8 - NC)
=
•
•
•
137 patients had
received 3 lines of
chemotherapy
tested with
local test
Subjects with response : 33.6%
ORR: 0.34 (0.26-0.42)
DoR: 7.9 (5.6 - 9.6)

Non significative difference between the results

Results are similar to those observed in the overall population

which supports effectiveness of the device
10
4

Risks are associated with the interpretation
of result testing:
False +


=> Not
clinical
benefit
=> Adverse
reactions of
olaparid
False –

=> not
obtain
olaparid
therapy
Delayed
results

=> delayed
in treatment
10
5
●
●
●
Benefit/Risk is favorable
BRACAnalysis Cdx is an aid in selecting patients
BRACAnalysis Cdx + Olaparib
●
–
Improvement in ORR and DoR
PMA accelerated approval on December, 19, 2014
with the drug Lynparza®
–
Additionnal testing of samples
–
Bridging study with ongoing clinical trial assay
10
6
Name Review
10
7
Office of
Prescription
Drug Promotion
CDER
Division of
Medication Error
Prevention and
Analysis
(DMEPA)
Evaluate the proposed proprietary name (PPN) :
from a safety and promotional perspective
1.
Promotional
Assessment
2.
Safety
Assessment
LYNPARZA®
10
8

OPDP evaluates PPN to determine if they are overly fanciful :
- misleadingly imply unique effectiveness or composition
- contribute to overstatement of product efficacy, minimization
of risk
- broadening of product indications, or making of
unsubstantiated superiority claims.
OPDP determined the PPN is acceptable from a promotional
perspective.
NB : DMEPA concurred with the findings of OPDP's promotional
assessment of the proposed name.
10
9



No United States Adopted Names (USAN) stem present in the
proprietary name
A single word with no derivation or intended meaning
→ Does not contain any components that are misleading or can
contribute to medication error
Two studies :
- FDA Name Simulation Studies
- Phonetic and Orthographic Computer Analysis (POCA)
11
0



No United States Adopted Names (USAN) stem present in the
proprietary name
A single word with no derivation or intended meaning
→ Does not contain any components that are misleading or can
contribute to medication error
Two studies :
- FDA Name Simulation Studies
- Phonetic and Orthographic Computer Analysis (POCA)
11
1

The orthographic appearance of the PPN is evaluated using a
number of different handwriting samples.

93 practitioners participated in the prescription studies

22 interpreted the name correctly as LYNPARZA®
11
2

Common
misinterpretations :
- letter « i » for « y »
(n=10)
- letter « Z » for « L »
(n=16)
These other
interpretations did
not overlap, sound
or look similar to
any currently
marketed products
11
3



No United States Adopted Names (USAN) stem present in the
proprietary name
A single word with no derivation or intended meaning
→ Does not contain any components that are misleading or can
contribute to medication error
Two studies :
- FDA Name Simulation Studies
- Phonetic and Orthographic Computer Analysis (POCA)
11
4

POCA = system designed by the FDA. Used to evaluate proposed
names via phonetic and orthographic algorithm.
LYNPARZA®
POCA score
= 100%
11
5

Moderately Similar Names with overlap or numerical similarity in
Strength and/or Dose
LYNPARZA®
LENTARD®
POCA
No.
Proposed name :
Proposed name :
Score
LYNPARZA®
LYNPARZA®
(%)
Strength : 50 mg
Strength : 50 mg
The infix and suffix of this
Usual Dose : 8 capsules
Usual Dose : 8 capsules
name pair have sufficient
(400 mg) by mouth twice
(400 mg) by mouth twice
orthographic differences.
daily
daily
The second syllabe of this
Clinpro 5000
52 pair has phonetic
7.
Lokara
name
differences and Lynparza
Flanders
52
8.
Lovaza
contains an extra syllable.
POCA
Score
(%)
3.
Lemtrada
57
9.
Lysteda
52
4.
Lentard
66
10.
******
50
No.
1.
2.
5.
6.
52
50
Lentard MC of the 24 names54contained
11. in Synera
50
Analysis
this table determined none
of
the names will pose a 52
risk for confusion.
Linjeta
12.
Translarna
50
11
6
1. Promotional
Assessment
2. Safety
Assessment
The proposed proprietary name is acceptable from both a
promotional and safety perspective.
11
7
Post
Marketing
Studies
REMS ?
11
8


Drug Safety and Risk Management Advisory
Committee
Advises on :
◦ risk management,
◦ risk communication,
◦ quantitative evaluation of spontaneous reports for
drugs
11
9

1.
In pivotal study : 223 patients treated
Adverse reaction reported in 20% or more of patients:
◦
◦
◦
◦
◦
◦
2.
3.
4.
anemia,
nausea,
fatigue (including asthenia),
vomiting,
diarrhea,
…
Adverse events in the clinical
trial program are similar to
those seen in clinical practice
with other chemotherapies
Laboratory abnormalities : 25% (Increase in creatinine,
decreases in hemoglobin,lymphocytes, absolute neutrophil
count, and platelets)
Adverse reactions led to dose interruption in 40% of patients,
dose reduction in 4%, and discontinuation in 7%.
Fatal cases of pneumonitis occurred in <1% of patients treated
addressed in Warnings and Precautions (similar to other
drugs used in the treatment of ovarian cancer)
12
0

Myelodysplastic syndrome (MDS)/Acute Myeloid Leukemia (AML)

The development of MDS/AML in recurrent ovarian cancer


Linked with the use of other DNA damaging chemotherapies
such as alkylating agents and platinum-based chemotherapies.
The rate of MDS in the general population according to data from
the National Cancer Institute’s (NCI) Surveillance, Epidemiology,
and End Results (Seer) program is approximately 3.3 per
100,000
12
1


When there are
fewer healthy
blood cells,
infection, anemia
, or easy
bleeding may
occur.
1/3 changes in
AML
12
2


In the overall clinical development program, MDS/AML were
reported in 22 of 2,618 (<1%) patients treated with olaparib, and
of these cases, 17/22 were fatal.
FDA reviewers note that the reported incidence of MDS/AML
in the olaparib database is higher than the expected
incidence in the general population and in an ovarian cancer
population treated with prior platinum-based therapies
12
3



Safety signal that warrants further investigation as a postmarketing requirement that may provide a better
characterization of this risk.
Provide annual summaries of all cases of AML/MDS identified
in patients treated with Lynparza (olaparib).
These reports should
◦ summarize all cases identified up until that reporting date (new cases and
those reported in previous years),
◦ include patients treated with Lynparza on clinical trials and outside of
clinical trials (including spontaneous safety reports)
12
4
Study/activity
(including study
number)
Objectives
Safety
concerns
/efficacy
issue
addressed
Status
Study 02, SOLO-2):
randomized doubleblind, placebocontrolled,
multi-center trial
to assess the efficacy of olaparib
maintenance monotherapy in :
-relapsed high grade serous ovarian
cancer (HGSOC) patients
-or high grade endometrioid cancer with
BRCA mutations who have responded
following platinum based chemotherapy
To provide
information on
the effect of
olaparib on
these patients
Ongoing
Study 10
a randomized trial
To establishg the superiority
of olaparib over physician’s choice single
agent chemotherapy in the treatment of
platinum sensitive relapsed ovarian
cancer in patients carrying deleterious or
suspected deleterious germline BRCA1/2
mutations
To provide
information on
the superiority
of olaparib
compared with
single agent
chemotherapy
Planned
12
5
Study/activity
(including study
number)
Objectives
Safety
concerns
/efficacy
issue
addressed
Status
Study 06
To assess the pharmacokinetics,
Safety and Tolerability of Olaparib
Following a Single Oral 300 mg
Dose to Patients with Advanced
Solid Tumors and Normal Renal
Function or Renal Impairment
To provide
information on
the use of
olaparib in
patients with
reduced liver
function.
Ongoing
(Submit the
final report)
Study 05
An Open-label,
Nonrandomized,
Multicenter,
Comparative,
Phase I Study
to determine the Pharmacokinetics,
Safety and Tolerability of Olaparib
Following a Single Oral 300 mg
Dose to Patients with Advanced
Solid Tumors and Normal Hepatic
Function or Mild or Moderate
Hepatic Impairment.
To provide
information on
the use of
olaparib in
patients with
reduced
hepatic
function.
Ongoing
(Submit the
final report)
An Open-label,
Nonrandomized,
Multicenter,
Comparative, and
Phase I Study
12
6
REMS is not necessary to ensure the benefits of olaparib
outweigh the risks in patients
•Accelerated approval procedure
•Since these risks are not uncommon or unknown to this
prescribing population, these risks can be communicated
through professional labeling.
12
7
Conclusion
12
8





Date of approval : december 2014 (first-in-class)
Indicated for monotherapy in patients with deleterious
or suspected deleterious germline BRCA mutated (as
detected by an FDA-approved test) advanced ovarian
cancer who have been treated with three or more prior
lines of chemotherapy
Companion diagnostic for BRCA mutation detection
Safety concerns : acute myelogenous leukemia and
myelodysplastic syndrome ► post-approval safety
studies
Futur other indications (breast, pancreas, prostate
cancers…) ?
Any questions?