Grégoire Franoux
                Licensing & Business Development
                      franoux@flamel.com



November 200...
Flamel At A Glance


 A Leading Drug Delivery Company.

 Founded in 1990 by a team of researchers from
  Rhone-Poulenc P...
Overview


 Two innovative technology platforms:
    –MICROPUMP® for oral small molecule drugs and
    –MEDUSA® for injec...
Flamel’s Partners

 Flamel has several ongoing MICROPUMP® partnerships
  including a global license and manufacturing agr...
MICROPUMP® Technology



            A very performing and flexible technology for the
               controlled-release o...
MICROPUMP® - Oral Delivery System for Small Molecules




   The microparticles are released in the stomach and pass into...
MICROPUMP® Meets Challenges
                for Delivery of Small Molecules

                   MICROPUMP® extends the re...
Carvedilol Microparticules
                Targeted releases to prolong the release




                           release...
MEDUSA® Technology



   An innovative biodegradable nanocarrier for the formulation
       and the delivery of a broad ra...
Comparison of long-acting formulations of biologics




                                   Protein Engineering            ...
Rationale for a new proteins delivery system

Flamel develops the Medusa Technology for the formulation and/or the
sustain...
Medusa® nanocarrier and protein adsorption



  Hydrophobic                                                      20 – 40 n...
Protein XL simplified formulation process


                                                                *: filtration ...
pK results in Dog: reproducibility of GMP batches
                    (Dose 60 µg/kg IFN, SC)




 IFN release extended t...
Solubilization of API with Medusa



                                                       [API ]
                       ...
MEDUSA® stabilizes therapeutic proteins


Example of improvement of hGH stability upon aggregation



     1          2   ...
Solubilization of protein (IL-2) using Medusa®



IL-2 with an isoelectric point 6.8 is insoluble at neutral pH.


IL-2 at...
IL-2 XL: pK response in human versus Proleukin

                                           6000
                          ...
Medusa: a wide range of applications



                           Peptides
                Insulin, PYY, GLP-1, Immuno-
 ...
Pessac Development and Manufacturing Facility




      AFSSAPS (French Agency), FDA approved site



November 2009       ...
Flamel, a unique and successful drug delivery company
                        with:

 One successful product on the marke...
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Flamel Short Corporate 2009

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Flamel Short Corporate 2009

  1. 1. Grégoire Franoux Licensing & Business Development franoux@flamel.com November 2009 Proprietary Information 1
  2. 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. 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. 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. 5. MICROPUMP® Technology A very performing and flexible technology for the controlled-release of small molecule drugs November 2009 Proprietary Information 5
  6. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 20. Pessac Development and Manufacturing Facility AFSSAPS (French Agency), FDA approved site November 2009 Proprietary Information 20
  21. 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

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