anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 christian bailly -...
TRANSCRIPT
![Page 1: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/1.jpg)
1 Christian BAILLY - Montpellier, October 2nd, 2015
Anti-cancer drug discovery: from bench to bedside
Christian BAILLY , [email protected]
Pierre Fabre CDMO
October 2nd, 2015
![Page 2: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/2.jpg)
2 Christian BAILLY - Montpellier, October 2nd, 2015
TARGETS&
MECHANISMS
MOLECULES
TOOLS &
MODELS
![Page 3: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/3.jpg)
3 Christian BAILLY - Montpellier, October 2nd, 2015
Target selection
ScreeningHits
Leadoptimisation
ExtensivePharmacol.
Preclinical Dev. Tox.
ProcessDev. Synth.
Phase Itrials
Phase IItrials
Phase IIItrials
Registration
Biology
Post-launchActivities
Drug Discovery Early Development
Clinical DevelopmentF.i.M.
Drug Discovery & Development
Commercial Act.
A long, difficult, multidisciplinary and expensive process
9-16 yearscost $~1 billion per successful product
Pharmaceutical R&DHigh risk, high costs
�����
![Page 4: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/4.jpg)
4 Christian BAILLY - Montpellier, October 2nd, 2015
Target selection
ScreeningHits
Leadoptimisation
ExtensivePharmacol.
Preclinical Dev. Tox.
Biology
Drug Discovery Early Development
Target selection and validation
- large panel of biochemical, biological assays
- establish the role of a target in the disease
- adressing the cellular pathway
- and the physiopathology
Screening, hit & Lead compounds
- target-based assays and HTS
- compounds management & selection
- extensive chemistry, SAR
- use of in silico approaches
- ADMET properties
- drug design, back up series
![Page 5: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/5.jpg)
5 Christian BAILLY - Montpellier, October 2nd, 2015
Target selection
ScreeningHits
Leadoptimisation
ExtensivePharmacol.
Preclinical Dev. Tox.
Biology
Drug Discovery Early Development
Pharmacology
- Mode of action, target modulation
- in vitro, in vivo activities
- ADMET profile
- Proof of Concept in animal
- Efficacy studies
- drug combinations
- PK/PD, metabolism
Preclinical Development
- Batch synthesis, (salts)
- Formulation, stability
- Toxicology studies: safety profile
- g/kg GMP synthesis, scale up
- complete chemical profile
+ dossiers
ProcessDev. Synth.
compound potential new medication
![Page 6: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/6.jpg)
6 Christian BAILLY - Montpellier, October 2nd, 2015
![Page 7: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/7.jpg)
7 Christian BAILLY - Montpellier, October 2nd, 2015
Targetvalidation
drugs, tools
Functions,efficacysafety
models
↓↓
↓↓ patients
TARGET SELECTION:
Scientific, Medical, Economical, & Strategic Considerations
Picking the right target is key… but confirmed only 10 years later
![Page 8: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/8.jpg)
8 Christian BAILLY - Montpellier, October 2nd, 2015
![Page 9: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/9.jpg)
9 Christian BAILLY - Montpellier, October 2nd, 2015
- by isolating active ingredients from traditional remedies
- by random screening of chemical libraries, including Nat. Prod.
- by rational design : based on understanding the metabolic pathways related to a disease state or pathogen, and manipulating these pathways using chemistry, mol./cell. biology and biochemistry
- by repositioning
- by serendipity …
penicillin
Drug Discovery
![Page 10: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/10.jpg)
10 Christian BAILLY - Montpellier, October 2nd, 2015
![Page 11: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/11.jpg)
11 Christian BAILLY - Montpellier, October 2nd, 2015How an accidental discovery paved the way for the treatment of complicated infantile haemangiomasA revolution in the management of infantile haemangiomas.
![Page 12: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/12.jpg)
12 Christian BAILLY - Montpellier, October 2nd, 2015
Drug screening & design
- High throughput screening : compound libraries, multi-well plates (96, 384,1536), robotics
- Knowledge-based rational design : computer modeling, structural analysis (NMR, X-ray crystal, etc), chemoinformatics…
- Hit optimisation, lead selection, drug candidate� iterative cycles of chemistry and biology (cpd MoA, potency, SAR, selectivity, stability…)
� Physicochemical properties (solubility, purity, complexity…)
� ADME, DMPK, imaging, in vivo profiling… � initial safety assesment (preliminary Tox, predictive Tox)
� innovation (I.P., patents): breakthroughs target/NCE, 2nd generation, formulation, etc…
� potential market, time to market (RoI)
� Molecular attrition: From « >100,000 » cpds to « 3-5 » pre-candidate� A major challenge to combine all desired properties into one molecule� … back-up and fllow up programs
![Page 13: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/13.jpg)
13 Christian BAILLY - Montpellier, October 2nd, 2015
![Page 14: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/14.jpg)
14 Christian BAILLY - Montpellier, October 2nd, 2015
- Search for "oncogenic drivers" and development of targeted therapies.
- Discovery of the EML4-ALK fusion gene in a subgroup (<5%) of patients with NSCLC (2007)
Rational Design: ALK inhibitors
- Accelerated approval of breakthrough therapy-designated drugs � Crizotinib in 2011, 2013 (Xalkori, Pfizer)
[4 years from the discovery of ALK rearrangement in NSCLC to the FDA approval]
� Ceritinib in 2014 (Zykadia, Novartis)
![Page 15: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/15.jpg)
15 Christian BAILLY - Montpellier, October 2nd, 2015
![Page 16: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/16.jpg)
16 Christian BAILLY - Montpellier, October 2nd, 2015
![Page 17: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/17.jpg)
17 Christian BAILLY - Montpellier, October 2nd, 2015
Structure activity relationship optimization campaig n
1 HTS hit � 50-300 derivatives � 1 optimized Lead
![Page 18: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/18.jpg)
18 Christian BAILLY - Montpellier, October 2nd, 2015
Models to evaluate mechanism of action & antitumor activity
![Page 19: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/19.jpg)
19 Christian BAILLY - Montpellier, October 2nd, 2015
Mitigating risk in academic preclinical drug discov ery. Dahlin et al., Nature Rev. Drug Discov. 14, 279-294 (2015)
![Page 20: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/20.jpg)
20 Christian BAILLY - Montpellier, October 2nd, 2015
![Page 21: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/21.jpg)
21 Christian BAILLY - Montpellier, October 2nd, 2015
Preclinical safety studies
- To explore the response at up to maximum achievable doses- To detect potential hazards and assess risks (general toxicology, geno-tox,
carcinogenicity, repro-tox, etc…)- To assist in dose-selection for initial clinical studies- To suggest markers to monitor safety in humans- To guide target-based investigations
- But not- to guarantee safety in humans- to predict human response- to define a mechanism
![Page 22: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/22.jpg)
22 Christian BAILLY - Montpellier, October 2nd, 2015
From molecules to medicines
� Chemical Development
� Pharmaceutical Development
![Page 23: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/23.jpg)
23 Christian BAILLY - Montpellier, October 2nd, 2015
Preformulation / API stress studies Formulation : selection of prototype for early clinical studies. Process development to select sterilizing method Formulation optimization (final strength) for commercial product.Scaling-up and process validation Long term stability studies
CMC: Chemistry, Manufacturing and Controls
Formulation development pH solubility and stability profilesAdditional preformulation studies : sensitivity to light,oxygen, temperature… Prototype formulation studies to select the best formulation based on stability studies (minimizing degradation products)Choice of the final strength for clinical and manufacturing
Process development Selection of the sterilisation method.Scale-up and process validationManufacturing clinical batches for clinical studies
![Page 24: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/24.jpg)
24 Christian BAILLY - Montpellier, October 2nd, 2015
Phase Itrials
Phase IItrials
Phase IIItrials
Registration Post-launchActivities
Clinical DevelopmentF.i.M.
USA: Investigational New Drug (IND) application:• Animal Pharmacology and Toxicology Studies - Preclinical data to permit an assessment as to whether the product is reasonably safe for initial testing in humans.• Manufacturing Information - Information pertaining to the composition, manufacturer, stability, and controls used for manufacturing the drug substance and the drug product.• Clinical Protocols and Investigator Information - Detailed protocols for proposed clinical studies to assess whether the initial-phase trials will expose subjects to unnecessary risks.
Europe: Investigational Medicinal Product Dossier (IMPD), for approval of clinical trials by the competent authorities
![Page 25: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/25.jpg)
25 Christian BAILLY - Montpellier, October 2nd, 2015
Phase Itrials
Phase IItrials
Phase IIItrials
Registration Post-launchActivities
Clinical DevelopmentF.i.M.
Phase I: First in Man
- Small group of healthy volonteers or patients
- determine the active dose or MTD
- Verify the mechanism of action: target modulation
- Determine a safe dose range and identify side effects
- Test potential biomarkers
+ prelimenary information on efficacyPhase II: Efficacy studies
- Larger group of patients (50-300)
- Evaluate activity, efficacy: POC
- Determine effective dose range
- Route and scheme of treatment
- Further evaluate the safety
- Biomarkers
- (combinations)
In general, heterogeneous tumor indications (s.t.)
Specific tumor indications- BC, NSCLC, PC, etc…
![Page 26: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/26.jpg)
26 Christian BAILLY - Montpellier, October 2nd, 2015
ProcessDev. Synth.
Phase Itrials
Phase IItrials
Phase IIItrials
Registration Post-launchActivities
Clinical DevelopmentF.i.M.
Phase III: Comparative studies
- Large group of patients (>500, >>)
- Comparative efficacy vs. used treatments
- Monitor side effects
- Dose range
- Safety
- Biomarker validation
Registration of a new drug
- Compile preclinical and clinical data
- Quality of data (biometry, statistics)
- manufacturing process
- submit NDA to regulatory authorities:
- quality + efficacy + safety
- NDA, from submission to approval:
� ~2 years (2 months–7 years)
� marketing authorization granted
� Launching, commercialization
Specific tumor indications- BC, NSCLC, PC, etc…
- pharmaco-economic impact- market value
![Page 27: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/27.jpg)
27 Christian BAILLY - Montpellier, October 2nd, 2015
ProcessDev. Synth.
Phase Itrials
Phase IItrials
Phase IIItrials
Registration Post-launchActivities
Clinical DevelopmentF.i.M.
Phase IV & post-lauch activities
- Drug on the market
- post-market surveillance
- Continue to monitor and report adverse effects
- Life-cycle mamagement: new indications and/or formulations
several years after the use in wide population, the risk remainsEx: rofecoxib (Vioxx), unacceptable cardiac side-effects � removed
![Page 28: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/28.jpg)
28 Christian BAILLY - Montpellier, October 2nd, 2015
R&D productivity over the past 60 years: on decline
![Page 29: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/29.jpg)
29 Christian BAILLY - Montpellier, October 2nd, 2015
![Page 30: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/30.jpg)
30 Christian BAILLY - Montpellier, October 2nd, 2015
CANCER is an attractive therapeutic field for pharmaceutical companies- new targets, multiple indications- high price of drugs « tolerated » (thus far)
But a field with a limited success: from F.i.M. to registration 90-95% attrition
The case of Oncology
![Page 31: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/31.jpg)
31 Christian BAILLY - Montpellier, October 2nd, 2015 (Nat. Rev. Drug Discov. 2004, 3, 675)
Drug repositioning
![Page 32: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/32.jpg)
32 Christian BAILLY - Montpellier, October 2nd, 2015
Ex: repositioning of anti-depressant drugs
depression fibromyalgia
![Page 33: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/33.jpg)
33 Christian BAILLY - Montpellier, October 2nd, 2015
injectable Navelbine oral Navelbine
vinorelbine (Navelbine®)vinorelbine (Navelbine®)
NH
NCH3
N
CH3
H
HOCH3
N
CH3 O
OO
CH3
O
CH3
OO
CH3OH
Vinorelbine
(1989) (2001)
Catharanthine+Vindoline
Anhydrovinblastine
![Page 34: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/34.jpg)
34 Christian BAILLY - Montpellier, October 2nd, 2015
NH
N
F
N
CH3
H
HO
CH3
N
CH3 O
OO
CH3
O
CH3
OO
CH3OH
CH3
FH
Vinflunine (JAVLOR®
)
� 1988: HF & vinca-alcaloïdes
� 1991: 50 mg of PM391
1994: in vivo activity
� 1996: vinflunine
� 1998: Phase I
� 2000: Phase II
2003: Phase III
� 2009: EMEA Approval, bladder cancer
![Page 35: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/35.jpg)
35 Christian BAILLY - Montpellier, October 2nd, 2015
(Lobert & Puozzo, Sem. Oncol. 2008, 35, S28)(Lobert & Correia, Methods Enzymol. 2000, 323, 77)
VFL: reduced affinity for tubulin dimers
« weak » affinity for tubulin� fewer and smaller spiral filaments � reduced neurotoxicity
![Page 36: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/36.jpg)
36 Christian BAILLY - Montpellier, October 2nd, 2015
VFL: high intra-cellular accumulation
- vinflunine
- vinorelbine
- vinblastine
- vincristine
(Lobert & Puozzo, Sem. Oncol. 2008, 35, S28)
![Page 37: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/37.jpg)
37 Christian BAILLY - Montpellier, October 2nd, 2015
Vinflunine activity in bladder cancer
DAYS AFTER TUMOR IMPLANTATION
PE
RC
EN
T S
UR
VIV
AL
vinflunine 20 mg/kg
vinflunine 10 mg/kg
vinorelbine 1.2 mg/kg
vinorelbine 0.6 mg/kg
saline
vinflunine 5 mg/kg
vinorelbine 2.4 mg/kg
vinorelbine 1.2 mg/kg
Control
VINFLUNINE 20 mg/kg
VINFLUNINE 10 mg/kg
vinorelbine 0.6 mg/kgvinorelbine 2.4 mg/kg
VINFLUNINE 5 mg/kg
Intravesically-implanted murine MB-49 bladder cancer
VFL increases lifespan of mice with bladder cancer
![Page 38: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/38.jpg)
38 Christian BAILLY - Montpellier, October 2nd, 2015
from Bellmunt et al., J. Clin. Oncol. 2009, August
![Page 39: Anti-cancer drug discovery: from bench to bedside · 2015-11-02 · 1 Christian BAILLY - Montpellier, October 2 nd, 2015 Anti-cancer drug discovery: from bench to bedside Christian](https://reader033.vdocuments.mx/reader033/viewer/2022041910/5e66d5121619961aee3cb829/html5/thumbnails/39.jpg)
39 Christian BAILLY - Montpellier, October 2nd, 2015
NH
N
F
N
CH3
H
HO
CH3
N
CH3 O
OO
CH3
O
CH3
OO
CH3OH
CH3
FH
Vinflunine (JAVLOR®
)
� 1988: HF & vinca alk.
� 1991: PM391
1994: in vivo activity
� 1996: vinflunine
� 1998: Phase I
� 2000: Phase II
2003: Phase III
� 2009: EMEA Approval, 1st indication