Download New TKI toward highly targeted therapies

TYROSINE
KINASE
INHIBITORS
Alice RENARD
Julie TELLIEZ
Valentin LEGROS
Oussama KAMAL
TKI taking off
Bcr-Abl
EGFR
VEGFR
Others
2
Kinase Signalisation Basis
1. Molecular level
Nobel Price
E. Fischer & E. Krebs (1992)
2. Celullar level
3. Phenotype level
Deregulation  Cancer, inflammation,
immunological and neurological diseases…
3
Signaling Pathways
Normal
(wild type)
Abnormalities
MODULATION
INHIBITION
JAK, Syk
Inflammation,
Autoimmunity
Bcr-Abl, EGFR
Companion
Diagnosis
+
Cancer
4
Signalling Pathways
Normal
pathways
MODULATION
JAK, Syk
Inflammation,
Autoimmunity
Abnormalities
INHIBITION
Bcr-Abl, EGFR
Companion
Diagnostics
+
Cancer
5
THE LONG ROAD TO
IMATINIB
6
Birth of Targeted Therapies
Beginning of
the biology
science at a
molecular
level
Oncogene
addiction
(dependency on
a single
oncogenic
protein or
pathway)
Side effects+
lack of activity
of cancer
treatment and
chemotherapy
radiations
Targeted therapies to enhance sensitivity:
PROTEIN KINASE INHIBITION
7
Drug Discovery
8
From random screening to
understanding
Bcr-Abl: the first
interesting target
for selective
chemotherapy
Imatinib: a breakthrough in
oncology
(96.6% responders
in IRIS)
9
A challenged discovery
Imatinib paved the way to a whole new era of tumor treatment :
Orally, targeted therapies
BUT ?...
 Competition with intracellular millimolar ATP concentration
 Selective, but not exclusive
 Resistance mecanism (31%)
- Missense mutations within the Abl kinase domain
- Over-expression of Bcr-Abl
10
Overcoming Resistances
Dealing with mutations…
… the 2nd generation Bcr-Abl inhibitors
Bosutinib
Bosutinib
FDA approval
2001
2007
2006
2012
10 – 100 times more potent than imatinib
11
2nd generation Bcr-Abl TKI
Imatinib (1st
generation)
Nilotinib
Dasatinib
Bosutinib
Binding of
the ABL-TK
Inactive
Inactive
Active
Active
conformation conformation conformation conformation
Inhibitor
type
2 (DFG out)
2
1
1
Selectivity
Bcr-Abl,
PDGFR, cKit
~ imatinib
Pan-TKI
Bcr-Abl +
KIT + Src
Spectrum
Limited
Every
common
mutation
Every
common
mutation
Even
broader
than the
others
T315I
gatekeeper
mutation
Insensitive
Insensitive
Insensitive
Insensitive
12
2nd generation Bcr-Abl TKI
Avantages
• Solve nearly all the mutationsrelated resistance problems
• Faster response rates
• Deeper responses + lower rate of
progression compared to imatinib
Drawbacks
• Not active against T315I
gatekeeper mutation
This mutation :
threonine -> isoleucine
(T315I) emergence as a
common pathway to
failure of both first &
second line treatments
13
3rd generation Bcr-Abl TKI
Targeting the T315I mutation
Ponatinib
•Pan Bcr-Abl inhibitor (WT+ t315i + other mutated
forms
•Binding to the inactive form + ethinyl linkage (C≡C)
•FDA-approved dec. 2012 ; Ariad
Rebastinib
•Phase I clinical trials
•Deciphera
Tozacertib
Danusertib
•Aurora-kinases inhibitors
•New 3rdG but high toxicity (presumably to be
discontinued)
14
Gefitinib – IRESSA®
15
Gefitinib Indication
-
Gefitinib has been the first EGFR-TKI approved in NSCLC
-
Gefitinib is indicated for locally advanced or metastatic non-small cell lung cancer
(NSCLC) in adult patients.
-
It targets EGFR-TK, which enable the development of the tumor.
16
Gefitinib Development
1.0
1.0
0.8
0.8
Proportion without
treatment failure
Proportion surviving
- The two first studies ISEL and INTEREST were unselected trials in pre-treated settings.
0.6
0.4
IRESSA
Placebo
0.2
ISEL Study
2003- 2005
0.6
0.4
0.2
0.0
0.0
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16
Months
Months
Objective Response Rate
8.0% vs 1.3%, p<0.0001
Thatcher 2005
17
Gefitinib Development
- After the results of the INTEREST study, FDA has restricted labelling of Iressa® in 2005.
INTEREST Study
2004- 2008
1.
0
IRESSA
Docetaxel
0.
8
0.
6
0.
6
0.
4
0.
4
0.
2
0.
2
0.
0 0
IRESSA
Docetaxel
0.
8
Probability of
progression-free
survival
Probability of survival
1.
0
4
8
12
16
20
24
Months
28
32
36
40
0.
0 0
4
8
12
16
20
24
28
32
36
40
Months
ORR [EFR population]: 9.1% IRESSA, 7.6% Docetaxel;
p=0.3257
Kim 2008
18
Gefitinib Development
-
In 2004, discovery of the relation between EGFR mutations and the response to Gefitinib.
-
In 2006 : start of IPASS study, with clinically selected trial in first line setting.
-
2009 : Gefitinib approved for the treatment
of clinically
or metastatic NSCLC
IRESSA
EGFR M+ advanced
(n=132)
with EGFR activating
mutations in second line therapy. Associated with EGFR mutation
Probability
1.0
Carboplatin / paclitaxel EGFR M+
oftest
PFSCobas® from Roche
(n=129)
0.8
EGFR M+
HR=0.48, 95% CI 0.36, 0.64
0.6
p<0.0001
0.4
Objective response
rate
71.2% vs 47.3%
0.2
p=0.0001
0.0
0
M+, mutation positive
4
8
12
16
Time from randomisation (months)
20
24
Mok 2009
19
Erlotinib - Tarceva®
20
Erlotinib Indication
-
Erlotinib is the first drug specifically approved for the treatment of EGFR activating
mutations in NSCLC.
-
Erlotinib is indicated for locally advanced or metastatic non-small cell lung cancer
(NSCLC) with EGFR activating mutations in adult patients in first line of treatment.
-
It has been developed with EGFR mutation test Roche cobas®.
21
Erlotinib Development
EURTAC phase III clinical trial
Erlotinib (n = 86)
Chemotherapy (n = 87)
HR = 0.37
Log-rank p < 0.0001
22
Erlotinib Development
-
2004 : Erlotinib is approved by the FDA for initial treatment of metastatic NSCLC for
patients with particular mutations of EGFR, that can be detected with an FDA approved
test.
-
2010 : Approved for maintenance of treatment for patients with metastatic NSCLC and
no progression after four cycles of platinium based chemotherapy.
-
2013 : Erlotinib is approved in first line of treatment for locally advanced or metastatic
NSCLC with EGFR activating mutations.
-
The first line has been approved with the Roche Cobas® test to detect EGFR mutations.
23
Roche Cobas® EGFR test
-
Cobas® tests are realised in a real-time PCR system : Cobas 4800 V 2.0.
-
Cobas® EGFR test detects exon 19 deletion and exon 21 substitution before treating
patients with Erlotinb.
-
This test is also used with Gefitinib and for dectecting BRAF V600E mutation for the
treatment of melanoma with this mutation.
24
Dabrafenib - Tafinlar®
25
Dabrafenib Indication
-
Dabrafenib is indicated for the treatment of unresectable or metastatic melanoma with
BRAF mutation V600E.
-
BRAF V600E mutation is the most common mutation with a prevalence of 90%. BRAF
mutations are present approximately in 60% of advanced melanomas.
-
Dabrafenib activity has been confirmed by suppressing ERK-P and decreasing cell
proliferation.
-
It has been developed with a detection test from bioMérieux : THxID BRAF.
26
Dabrafenib Development
-
Dabrafenib has been approved by the FDA and the EMA in 2013 as a NME.
-
It has a major activity on BRAF V600E but also on BRAF V600K mutation.
-
It has been developed with a detection test from bioMérieux : THxID BRAF that detects
both V600E and V600K mutations.
27
THxID® BRAF test
-
THxID BRAF has been developed through the collaboration of bioMérieux and GSK.
-
The test is approved by the FDA since may 2013 and is CE marked.
-
It has the same detection mechanism of BRAF mutations than Cobas® : a real time PCR
system, but has been developed only for detecting BRAF mutations.
28
Summary
--tinib
Gefitinib
Erlotinib
Gefitinib
2002
2004
2009
Unspecific
development and
clinical trials
Specific
development and
clinical trials
without
companion
diagnostic
Specific clinical
trials to have a
specific
indication
Dabrafenib
2013
Specific
development and
clinical trials
with a
companion
diagnostic
2013
29
Regulatory Landscape
• Ensuring the safe and effective delivery of molecularly targeted
agents
• Status : IVD
• July 14th, 2011 draft
guidance :
Targeted oncology agents
would only gain approval if
reviewed in parallel with
companion diagnostic tests.
• Status : IVD
• IVD directive 98/79/EC :
Certification process (CE) by
an EU Notified Body.
• IVD directive is currently being
re-written.
• Classe C rating.
30
Regulatory Landscape
Manufacturer
submits file
Notified Body
Approval
Board
Notified Body
Notified Body
Review
31
CDx Perspective
• Historical perspective : Most of CDx developed after
“companion” drug with a retrospective validation.
• Draft Guidance : “In most circumstances, if use of an in vitro
companion diagnostic device is essential for the safe and
effective use of a therpeutic product, the IVD companion
diagnostic device and therapeutic product should be
approved or cleared contemporaneously by FDA for the
use indicated in the therapeutic product labeling”
•
ZELBORAF :
•
Advanced
Melanoma
•
Approved
in 2011
•
XALKORI :
•
NSCLC
•
Apporved
in 2011
32
CDx Perspective
33
Co-development Value
Stake Holder
Benefit
BioPharma
•
Reduce drug development costs
Companies
•
Improve efficacy-safety profile of drug
•
Increase cost-effectiveness profile
•
Accelerate approval
•
Premium pricing for targeted drug
•
Premium reimbursement
CDx
•
New market opportunities
Companies
•
New partnership Biopharma-CDx companies
•
Premium pricing for CDx
34
l
CDx Market
35
Global Diagnostic Market
Key Players
• $45 Bn in 2012
• +5% of growth to $62 Bn in
2016
17%
Roche
• Key Market Players :
•
•
•
•
Roche : $7.5 Bn
Siemens : $5.2 Bn
Danaher : $4.4 Bn
Abbott : $4.3 Bn
11%
Siemens
Danaher
52%
10%
10%
Abbott
Others
36
Global CDx Market
• $22 Bn of companion drugs sales
• Key Market Players :
• Roche Laboratories
• Novartis
• Pfizer.
4%
Sales Revenue
Other
Diagnostics
96%
Companion
Diagnostics
62% of the companion drugs market.
• $1.8Bn of CDx sales
• US market : 40% of global CDx market.
• Annual Growth 21.6%
37
New Pharmaceutical Landscape
• Emergence of a « Life Science Majors » (Roche, Abbott…) :
 Roche :
• Integrate the 3 key of the CDx-drug Market ( Drug
development, Diagnostics, Devices).
• Business Model : “In-house” development.
• Co-development Drug-CDx.
• 4 Business Models :




“In-house” Dx division
Dx Business Unit – Pharma
Dx development group
Life sciences research division.
• Strong strategic Partnerships :
 Manage complex development projects.
 New strategic partnerships : Pharma-Academic R&D (focused on
biomarker discovery).
38
Perspectives
Short Term
Medium Term
Long Term
< 3 years
3-10 years
> 10 years
Oncology
Diabetes
Metabolic
Solid and blood
cancer
Thrombosis
Stroke
Depression
Autoimmunity
Inflammation
Chronic Pain
Dementia
39
l
CDx Perspectives
40
CDx development Hurdles
• Financial and economic risk of co-development drug-CD :
early development failure.
• The co-development drug-CD process is complex.
• Small targeted market.
• Impact on the Pharma business model.
• Global regulatory landscape : Heterogeneous and continually
changing.
• Heterogeneous HealthCare/Reimbursement System in the
EU.
41
Signaling Pathways
Normal
pathways
MODULATION
JAK, Syk
Inflammation,
Autoimmunity
Abnormalities
INHIBITION
Bcr-Abl, EGFR
Companion
Diagnostics
Cancer
42
Rheumatoid Arthritis
Greater understanding of
inflammatory signalling cascades
JAK
Syk
Tofacitinib
Fostamatinib
43
Rheumatoid Arthritis
Context
Painful, systemic, chronic inflammatory disease
 damage to the joints, connective tissues, muscles, tendons
Inflammatory cytokines (IL, IFN, GF)
 activation of Janus Kinases (JAKs)
↗ JAK 1 & 3 expression in the synovium of
patients with RA
First to be tested « jakinib »
Tofacitinib
44
Tofacitinib
Mechanism of action
JAK1 & JAK3 potent antagonist
• JAK3  γc family cytokines
• JAK1  γc cytokines, IF, IL-6
 inhibits innate immune responses :
macrophages, proinflammatory cytokines,
potent effects on lymphocytes
 ↘ inflammation
45
Tofacitinib Approval
First oral Kinase Inhibitor approved
for the treatment of rheumatoid arthritis :
• FDA approval in 2012 : treatment of adult patients with moderately to severely active
rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate
• Studies to evaluate efficacy in other inflammatory immune-mediated disease :
- Phase III : Psoriasis , Ulcerative colitis
- Phase II : Crohn’s disease
- Phase I : Juvenile Idiopathic Arthrosis
46
Tofacitinib
• Superiority VS placebo,
non-inferiority VS adalimumab
• FDA warning box for serious
infections and malignancies
• Oral agents  many patients do not
respond to biologic therapies
• FDA approval with a Risk
Evaluation and Mitigation
Strategy (REMS)
• Clinical trials in psoriasis, ulcerative
colitis, Crohn’s disease  potentially
attractive
• Blockage of cytokines involved in the
pathogenosis of systemic lupus
erythematosus
 could reprensent another setting
• Long-term, large-scale and
high-quality postmarketing
research is necessary to
further verify the conclusion
• Not approved by the EMA :
concerns about safety profile :
type and risks of serious
infections
47
Other JAK inhibitors in RA
Baricitinib
Ruxolitinib
• JAK 1 & 2 inhibitor
• JAK 1 & 2 inhibitor
• Phase III clinical trials  RA
• FDA approval  myelofibrosis
 polycythaemia vera
• Phase II  diabetic nephropathy
 psoriasis
• Phase II clinical trials  RA,
psoriasis, essential thrombocythaemia,
acute leukaemia, lymphoma, multiple
myeloma, prostate cancer, breast cancer
48
Rheumatoid Arthritis
Greater understanding of
inflammatory signalling cascades
JAK
Syk
Tofacitinib
Fostamatinib
49
Fostamatinib : a promising Syk inhibitor
Syk
important mediator of immunoreceptor
(Fcγ) signalling in macrophages,
neutrophils, mast cells, and B cells
also present in the
synovium of patients with
Rheumatoid Arthritis
 critical roles in the
mechanisms of immunity
and inflammation
50
Fostamatinib development

Phase II trials :
fostamatinib therapy was generally well tolerated
 2010 : Partnership with AstraZeneca (potential as a first-in-class oral alternative to
current injectable RA drugs)

Phase III trials :
• OSKIRA 1 : VS placebo in patients responding inadequately to Methotrexate
=> one of the two primary endpoints reached
• OSKIRA 2 : VS placebo in patients responding inadequately to DMARDs*
=> significant improvements
• OSKIRA 3 : VS placebo in patients responding inadequately to TNFα antagonist therapy
=> significant improvements in one group of two
• OSKIRA 4 : VS placebo (superiority) : significant improvements in one group of two
VS adalimumab (non inferiority) : failed to match the efficacy of adalimumab
* DMARDs: Disease Modifying Anti-Rheumatoid Drugs
51
Fostamatinib : an end in failure ?
Failure in clinical trials
• AstraZeneca handing rights
for the drug back to Rigel
• Rigel has now given up completely
on the development of fostamatinib
for the treatment of RA
 insufficient efficacy findings
 “competitive landscape”
New opportunities
• Phase II clinical study in Immune
Thrombocytopenic Purpura (ITP)
showed positive results in patients
Phase III study in the first half of 2014
• Phase II study for Immunoglobulin A
Nephropathy (IgAN) in spring 2014
52
New Indications TKI
Tofacitinib
Baricitinib (Ph III)
Rheumatoid
Arthritis
JAK
Idiopathic
Pulmonary
Fibrosis
PDGF, VEGF,
FGF
Nintedanib (Ph III)
Immune
Thrombocytopenic
Purpura
Syk
Fostamatinib (Ph III)
JAK
Tofacitinib (Ph III)
Psoriasis
53
New indications TKI : far from being a success…
Success
Waiting for
clinical results…
Rheumatoid
Arthritis
Idiopathic
Pulmonary
Fibrosis
Psoriasis
Immune
Thrombocytopenic
Purpura
Very first steps…
Alzheimer’s
Disease
Diabetic
Nephropathy
Lupus Systematic
Erythematosus
Juvenile
Idiopathic
Arthrosis
Allergic
Asthma
Glaucoma
Allergic
Rhinitis
54
Conclusion
• Birth of targeted therapies : Imatinib -> TKI development
• Targeting more precisely the mutations : Companion Diagnostics
• Cancer and Inflammation : Interlinked pathways
Cancer
Inflammation
55
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References
- Drug development to overcome resistance to EGFR inhibitors in lung and colorectal cancer Rodrigo Dienstmanna,*,
Sara De Dossob, Enriqueta Felipa, Josep Taberneroa Molecular Oncology 6 (2012) 15e2 6
- Cellular Targets of Gefitinib Dirk Brehmer,1 Zolta´n Greff,2 Klaus Godl,1 Stephanie Blencke,1 Alexander
Kurtenbach,1 Martina Weber,1 Stefan Mu¨ller,1 Bert Klebl,1 Matt Cotten,1 Gyo¨rgy Ke´ri,2,3 Josef Wissing,1 and
Henrik Daub1Cancer Res 2005; 65(2): 379-82.
- Cobas EGFR mutation Test.
- CHUGAI PHARMACEUTICAL CO., LTD. Lifecycle Leader (Tarceva) Oncology Disease Area Dept. Strategic
Marketing Unit Koh Sato 2005.12.16
- Anne De Bock Portfolio Leader, Oncology/Infection European Regulatory Affairs AstraZeneca
- Dabrafenib RCP - EMA
57
References
• http://www.ariis.fr/wp-content/uploads/2011/03/biomarqueurs-etude-versioncomplete-130-slides.pdf
• http://www.ddw-online.com/personalised-medicine/p92845-overview-ofcompanion-diagnostics-in-the-pharmaceutical-industry.spring-10.html
• http://www.fiercemedicaldevices.com/story/roche-bets-big-companiondiagnostics/2012-09-05
• http://www.medscape.com/viewarticle/804156
• http://www.reportlinker.com/p01361266/Companion-DiagnosticsMarket.html#utm_source=prnewswire&utm_medium=pr&utm_campaign=Diagn
ostics
• http://www.fdanews.com/articles/149287-ema-to-wait-for-more-experiencebefore-issuing-guidance-on-companion-diagnostics
• http://www.ema.europa.eu/ema/
• http://www.fda.gov/
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•
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•
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•
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•
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•
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Essais cliniques de phase III randomisés : 717
patients ayant reçu préalablement du
Methotrexate(3), répartis en 4 groupes qui ont
reçu respectivement :
- le Tofacitinib 5mg
- le Tofacitinib 10mg
- l’Adalimumab (2)
- un placebo
En termes d’efficacité, le
tofacitinib démontre une
supériorité significative par
rapport au placebo et
une non-infériorité par
rapport à l’adalimumab.
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