1. Grégoire Franoux
Licensing & Business Development
franoux@flamel.com
November 2009 Proprietary Information 1

2. Flamel At A Glance
 A Leading Drug Delivery Company.
 Founded in 1990 by a team of researchers from
Rhone-Poulenc Polymer Division.
 Headquartered in Venissieux, France (near Lyon).
 Publicly traded on Nasdaq (FLML) since 1996.
 300 employees (75% in R&D and Production).
 Strong commitment to science and innovation.
 Solid cash position, no debt.
November 2009 Proprietary Information 2

3. Overview
 Two innovative technology platforms:
–MICROPUMP® for oral small molecule drugs and
–MEDUSA® for injectable proteins and peptides
 +12 Flamel products have undergone successful human clinical
trials
 FDA approved MICROPUMP® project with GlaxoSmithKline
(GSK), for controlled release Carvedilol (Coreg CR®).
 Flamel is a partnership-oriented Drug Delivery Company:
Flamel’s proprietary technologies may be applied in partnership
to improve new chemical entities, new proteins or currently
approved drugs.
November 2009 Proprietary Information 3

4. Flamel’s Partners
 Flamel has several ongoing MICROPUMP® partnerships
including a global license and manufacturing agreement with
GSK for Coreg CR®
 Flamel has ongoing MEDUSA® partnerships with 8 of the
TOP-25 Pharmaceutical Companies worldwide including:
November 2009 Proprietary Information 4

5. MICROPUMP® Technology
A very performing and flexible technology for the
controlled-release of small molecule drugs
November 2009 Proprietary Information 5

6. MICROPUMP® - Oral Delivery System for Small Molecules
 The microparticles are released in the stomach and pass into the small intestine, where
each microparticle releases the drug by osmotic pressure
November 2009 Proprietary Information 6

7. MICROPUMP® Meets Challenges
for Delivery of Small Molecules
 MICROPUMP® extends the release of drugs best
absorbed in the small intestine (75% of all drugs)
 9 molecules are proven in human clinical trials:
– Lansoprazole SR
– Omeprazole XL
– Genvir™ (acyclovir SR)
– ASACARD® (aspirin SR) Approved in Europe
– Metformin XL
– Augmentin SR
– Coreg CR® (Carvedilol CR) Marketed by
– Undisclosed cardiovascular drugs
 Versatile presentation to serve all markets from
pediatric to geriatric
– Suspensions
– Capsules
– Tablets
– Sachets
November 2009 Proprietary Information 7

8. Carvedilol Microparticules
Targeted releases to prolong the release
release in the stomach
CR Microparticules: Once-Daily PK Profile
release in the intestine
C24
Carvedilol
plasma
concentration
0 hr 12 hr 24 hr
November 2009 Proprietary Information 8

9. MEDUSA® Technology
An innovative biodegradable nanocarrier for the formulation
and the delivery of a broad range of biotherapeutics
November 2009 Proprietary Information 9

10. Comparison of long-acting formulations of biologics
Protein Engineering Microspheres Depot MEDUSA®
(PEGylation, Albumin Fusion…) (PLA / PLGA… )
Non-immunogenic +/-  
Bioactivity maintained   
Fully biodegradable +/- +/- 
Good local tolerance   
Applicable to large and fragile
Proteins   
Applicable to Peptides   
Simple low-cost process, easy
to scale-up   
Robustness / Reproducibility  +/- 
Yield +/-  
November 2009 Proprietary Information 10

11. Rationale for a new proteins delivery system
Flamel develops the Medusa Technology for the formulation and/or the
sustained release of therapeutic proteins and peptides.
The Technology is based on self-association of proteins or peptides with
polyaminoacid nanocarriers.
Unique advantages:
 The biological activity is maintained: no modification of
the carried therapeutic protein /peptide.
 The safety profile is improved: a lower Cmax and a more
regular concentration profile.
 Potential improvement of therapeutic benefit.
 Ability to solubilize and stabilize insoluble and/or unstable
proteins/peptides and prevent their aggregation.
November 2009 Proprietary Information 11

12. Medusa® nanocarrier and protein adsorption
Hydrophobic 20 – 40 nm
Vitamin E group
Hydrophobic
COONa COONa
nanodomain
COONa COONa
COONa
COONa
Protein or
peptide
Hydrophilic biodegradable
poly-Glu chain
Self-association of
protein/peptide with
Medusa nanoparticle
* No chemical bond
November 2009 Proprietary Information 12

13. Protein XL simplified formulation process
*: filtration 0.22 µm on sterile
membrane
Polymer solution pH, salt adjusted *
30 mg/mL
Protein solution *
Mixing @ 25°C
Protein XL Filling
Storage
Protein friendly process
 No organic solvent
 No shear, no heat
November 2009 Proprietary Information 13

14. pK results in Dog: reproducibility of GMP batches
(Dose 60 µg/kg IFN, SC)
 IFN release extended to 6 days
 Robustness of the pK profiles (5 # GMP batches made at 1 L scale,
at different times and with different CROs...)
November 2009 Proprietary Information 14

15. Solubilization of API with Medusa
[API ]
Solubility of API Solubility
solubilized
without additive increase
(mg/ml)
(mg/ml)
With Medusa
Carvedilol 0.021-0.060 36 x 700
Simvastatine
0.013-0.050 19.2 X 1100
Nifedipine
0.010 1.8 X 180
Ketoconazole 0.010 1.2 X 120
Opioid 0.010 15 X 1500
Paclitaxel 0.001 4.8 X 4800
November 2009 Proprietary Information 15

16. MEDUSA® stabilizes therapeutic proteins
Example of improvement of hGH stability upon aggregation
1 2 3 4 1: 5 mg/mL hGH
2: 5 mg/mL hGH/Medusa
3: solution 1 vigorously shaken
Aggregation
4: solution 2 vigorously shaken
 Medusa masks hydrophobic patches of hGH.
 Medusa prevents physical aggregation of hGH.
November 2009 Proprietary Information 16

17. Solubilization of protein (IL-2) using Medusa®
IL-2 with an isoelectric point 6.8 is insoluble at neutral pH.
IL-2 at pH 7.2:  INSOLUBLE (solubility < 0.3 mg/ml)
IL-2/HMpGlu at pH 7.2:  SOLUBLE up to 10 mg/ml
 Medusa improves the IL-2 solubility (loading up to 50% wt/wt)
while preserving the full bio-activity of the protein.
November 2009 Proprietary Information 17

18. IL-2 XL: pK response in human versus Proleukin
6000
Medusil (Il-2-XL)
Proleukin
5000
•Treatment A : 10.6*106IU/m2 Proleukin
seric Il-2 concentration (pg/ml)
4000
•Treatment B : 10.6*106IU/m2 IL-2 XL
3000
2000
1000
0
0 1 2 3 4 5 6 7 8
times (days)
Sustained release of IL-2 demonstrated (decrease of Cmax (2.4 fold);
increase of Tmax).
In addition, AUC is also increased ( +60%).
The pharmacokinetic profile supports the once a week administration
November 2009 Proprietary Information 18

19. Medusa: a wide range of applications
Peptides
Insulin, PYY, GLP-1, Immuno-
≤7 peptides…
Medium-sized Proteins
7≤X≤100 Hormones (hGH…) , Cytokines
(IFNs, interleukins…), Fab’,
Antigens…
Large Proteins
≥100 Enzymes, Antibodies, Blood
coagulation factors…
KDa
November 2009 Proprietary Information 19

20. Pessac Development and Manufacturing Facility
AFSSAPS (French Agency), FDA approved site
November 2009 Proprietary Information 20

21. Flamel, a unique and successful drug delivery company
with:
 One successful product on the market, validating Flamel’s know-how
and technologies (GSK’s Coreg CR)
 More than 15 ongoing innovative formulation projects financed by
different pharmaceutical partners
 Breakthrough technologies for the formulation and the delivery of the
next-generation of biotherapeutics
 A world-class team of polymer and formulation researchers with
unsurpassed experience in the drug delivery field
 Significant and growing intellectual property portfolio (more than 60
patent families)
 An FDA/Affsaps approved pharmaceutical plant for scale-up and
commercial manufacturing
 A very solid financial position
 A nimble approach to collaboration structures with pharmaceutical and
biotech companies
November 2009 Proprietary Information 21