Forward Looking Statements
The following presentation regarding Flamel Technologies SA includes a number of matters, particularly as related to the status of various research projects and technology platforms, that constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995.
presentation reflects the current views of Flamel's management with respect to future events and is subject to risks and uncertainties that could cause actual results to differ materially from those contemplated in such forward-looking statements. These risks include risks that products in the development stage may not achieve scientific objectives or milestones or meet stringent regulatory requirements, uncertainties regarding market acceptance of products in development, the impact of competitive products and pricing, and the risks associated with Flamel's reliance on outside parties and key strategic alliances. These and other risks are described more fully in Flamel's public filings. Except as required by law, Flamel does not intend, and disclaims any duty or obligation, to update or revise any forward-looking statements contained in this presentation to reflect new information, future events or otherwise. Flamel’s Comparative Advantage
Flamel was founded in 1990 to develop technologies based on its expertise in polymer chemistry.
Two Best in Class Drug Delivery Platforms:
• Micropump for Small Molecules:
– Chosen by GSK to defend Coreg® franchise.
• Medusa for Proteins and Peptides:
– Allows controlled release without loss of bioactivity.
Flamel’s proprietary technologies may be applied in partnership to improve:
• New chemical entities. • New proteins or currently approved drugs.
Flamel also develops projects through proof of concept using its
Flamel’s Business Model
Flamel selects and licenses its products to partners capable of developing them and maximizing their market value:
• We benefit from large companies’ depth of experience in managing
clinical trials, the registration process, and its sales force.
• Partners benefit from our focus on drug delivery technology and our
ability to develop and, if necessary, manufacture on tight timetables.
Flamel receives upfront payments, milestones and royalties based on the partner’s sales.
Flamel retains a right to recover the project if the partner decides not to develop or to market it.
Goal is for partnership development revenues and milestones to be used for internal projects, allowing royalty revenues to flow directly to earnings. Micropump®: Controlled Release of Small Molecule Drugs for Better Efficacy and Compliance Micropump® - Oral Delivery System for Small Molecules Core: active ingredient Coating: 200-500 µm Size Matters Advantages of the Micropump® System
Transit time in the small intestine is extended (up to 12 hours), allowing
greater flexibility in treatment, such as chronotherapy.
Bioavailability improvements are possible for drugs with poor bioabsorption. Intersubject and intrasubject variability is minimized. Versatile presentation to serve all markets from pediatric to geriatric with
• Suspensions• Capsules• Tablets• Sachets
High Drug Loading Ratio. Enables the delivery of low-solubility or high-solubility drugs. Combination therapy is facilitated, as each microparticle is its own delivery The majority of small molecule drugs are candidates for Micropump® COREG-CR™: Partnered Product with COREG CR™ Therapeutic Indications & Advantages Indicated for:
Mild to Severe Congestive Heart Failure.
Left Ventricular Dysfunction Following Myocardial Infarction. Partnership
Coreg 2006 sales were over $1.4 billion and grew at 38%:
• 1H 2007 annualized sales for the Coreg franchise were $1.65 billion.
Growth has been driven by Coreg’s success in treating congestive heart failure (CHF):
• Only beta-blocking agent FDA approved to improve survival in mild to
• Only beta-blocker approved for reducing cardiovascular mortality in Post MI
patients with left ventricular dysfunction.
We are the exclusive supplier for Coreg-CR microparticles using our Micropump® platform:
• Plant capacity in Pessac was expanded at GSK’s cost. • Second supply agreement announced August, 2006 to increase capacity by 50%. • Potential further capacity expansion. Four Catalysts for Success of COREG CR COREG CR’s unique release profile creates therapeutic benefits PK Equivalence: Mean Steady-State Plasma Concentration- Time Profiles for COREG and COREG CR in LVD Patients edilol (ng/mL) rv COREG CR 80 mg QD (n= 42) COREG 25 mg Q12h (n= 42) Time (hours)
Packer M et al. Am J Cardiol. 2006;98:39L–45L. In a 122 patient crossover study, patients initially receiving COREG CR reported 24% fewer adverse events than patients receiving regular Coreg.
Articles from American Journal of Cardiology 2006, 98
1. Pharmacokinetic Properties of a New Controlled-Release Formulation of Carvedilol: David Tenero et al.
2. Pharmacokinetic Profile of Controlled-Release Carvedilol in Patients with Left Ventricular Dysfunction
Associated with Chronic Heart Failure of After Myocardial Infarction: Milton Packer et al.
3. Pharmacokinetic and Pharmacodynamic Comparison of Controlled-Relesae Carvedilol and Immediate
Release Carvedilol at Steady State in Patients with Hypertension: Linda Henderson et al.
4. Controlled-Release Carvedilol in the Treatment of Essential Hypertension: Michael Weber et al.
5. Cardiovascular Risk Factors in Hypertension: Rationale and Design of Studies to Investigate the Effects
of Controlled-Release Carvedilol on Regression of Left Ventricular Hypertrophy and Lipid Profile: George
6. Rationale and Design of CASPER: Compliance and Quality of Life Study Comparing Once-Daily Carvedilol
CR and Twice-Daily Carvedilol IR in Patients with Heart Failure: Paul Hauptman et al.
7. COMPARE: Comparison of the Effects of Carvedilol CR and Carvedilol IR on Left Ventricular Ejection
Fraction in Patients with Heart Failure: Barry Greenberg et al.
8. Effect of Beta Blockers, Particularly Carvedilol, on Reducing the Risk of Events After Acute Myocardial
9. Controlled-Release Carvedilol: A Concluding Perspective: Milton Packer. COREG CR versus Coreg®: the COMPARE Trial
A study to compare the Effects of Coreg CR and Coreg IR on Heart
Function in Subjects with Stable Chronic Heart Failure:
- 700 patients with stable heart failure. - Compares left ventricular ejection fraction to baseline six months post-
- Change in left ventricular remodelling;- Change in Brain Natriuretic Peptide (BNP) level;- Hospitilizations fro heart failure;- Drug dose tolerability; and- Compliance
Diabetes and Hypertension
Over 13 million Americans have both diabetes and hypertension:
• It is estimated that over 65% of these patients require treatment with
two or more different anti-hypertensive medications at recommended
levels to reach suggested blood pressure levels.
The American Diabetes Association recommends diabetic patients should be treated to a systolic/diastolic level of <130/80:
• Hypertension is typically defined as blood pressure greater than 140/85. Coreg is the only approved beta blocker shown not to raise glycemia levels and to increase insulin sensitivity in diabetic patients. COREG CR Hypertension Trials COREG CR + Lisinopril Combination Trials:
• The CLEVER study – COREG CR and left ventricular mass regression:
- 200 patients with Stage 1 or 2 hypertension and left ventricular hypertrophy.
• COREG and Lisinopril Combination Therapy in Hypertensive Subjects (COSMOS) Trial:
- 643 patients with Stage 1 or 2 hypertension.
• The Vascular Effects of Carvedilol CR + Lisinopril Versus Lisinopril + Hydrochlorothiazide
in Abdominally Obese Hypertensive Patients.
• Vascular Benefits of Adding Carvedilol CR to Type 2 Diabetic Patients on ACEI.
• COREG CR Monotherapy Trial:
COREG CR vs TOPROL-XL on the lipid profile of normolipidemic or mildly dyslipidemic
RING FENCES PROTECT COREG CR IP
Notice of Allowance issued by United States Patent and Trademark Office March 23, 2007:
• To cover carvedilol dihydrogen phosphate hemihydrate through
• At least eight other claims reserved.
Micropump I Formulation Patents extend to 2016.
Micropump II Formulation Patent in Prosecution to extend to 2023.
Hatch Waxman Exclusivity on Coreg CR to extend at least three
New possible combination products to receive further potential Hatch Waxman exclusivity as well. Abuse of Opioid analgesics: the Trigger Lock™ Solution First Do No Harm
All opioid analgesics face considerable abuse:
• Leads to potential under-treatment of severe pain. • Legal and regulatory ovesight of this market is increasing.
Trigger Lock is designed to deliver sustained release of drugs susceptible to abuse:
• Microparticles effectively cannot be crushed• Dissolution in alcohol and other domestic solvents reduced• Injection is effectively impossible• Possible application for Oxycontin® ($2.0 billion in US sales in 2004)
Trigger Lock allows us to formulate these drugs without affecting bioavailability:
• Potentially greater efficacy than existing platforms• Ability to introduce bioequivalent formulations of existing products due to pharmacokinetic
advantage versus other abuse resistant technologies
Two Phase I trials are planned:
• To demonstrate bio-equivalence versus a commonly prescribed controlled release opioid analgesic. • To demonstrate resistance to alcohol-related dose dumping. Medusa® Third Generation Technology for Delivery of Unmodified Human Proteins Description of Medusa® II nanocarrier Evolution of Therapeutic Protein Formulations
Generation I - Immediate release proteins:
• efficacy of human proteins,• strong side-effects,• numerous injections per week.
Generation II - PEGylation:
• reduces the number of injections per week,• decreases the bioactivity of the protein,• strong-side effects.
MEDUSA allows the creation Third Generation Therapeutic Proteins and
• maintains efficacy of human proteins with full bioactivity,• reduces the number of injections per week, and• reduces-side effects. The Ubiquitous Polymer
The latest Medusa polymer is applicable to a wide variety of
proteins, peptides, and other large molecules
All pre-clinical toxicology and carcinogenicity tests have
Use of a single polymer speeds development time and saves
Four new projects using the new Medusa polymer:
–Oncology;–Therapeutic Vaccine;–Ophthalmology;–Therapeutic Protein
License Agreement with Wyeth Pharmaceuticals
To develop an improved formulation of an already marketed
•Upfront payment;•Development costs to be paid by Wyeth;•Milestones; and•Royalties
IFN-Alpha XL Viral Load Result (non-responder patients) og L ( n tio Time (Hours)
Viral load decrease in non-responding genotype 1 patients:
IFN XL: Safety viraferon (3*3MIU) Hematological Influenza like Illness IFN-XL is well tolerated: adverse events were transient and slight to moderate in severity FT-105 Next Generation Basal Insulin
Phase I glucose clamp study versus Lantus® ongoing.
Preclinical results indicate 48 hour controlled release.
Promises true 24 hour coverage for 100% of patients with better
glucose control than the best in class. Financial Summary Six months ended Six months ended June 30, 2006 June 30, 2007 Board of Directors Elie Vannier Chairman Cornelis (Cor) Boonstra Director
(Former Chairman and Chief Executive Officer of
Frédéric Lemoine Director Lodewijk J.R. de Vink Director
(Former Chairman and Chief Executive Officer of Warner Lambert
and Former President of Schering Plough International)
John L. Vogelstein Director Stephen H. Willard Director and CEO
Experimental and Clinical Evidence for Brimonidine as an Optic Nerve and Retinal Neuroprotective Agent An Evidence-Based Review Meredith Saylor, BA; Linda K. McLoon, PhD; Andrew R. Harrison, MD; Michael S. Lee, MD Objective: To review the available evidence for the neu- for neuroprotection: receptors on its target tissues, ad-roprotective qualities of brimonidine tartrate in optic ne
Asunción Alba (UNED) ● Román Álvarez (University of Salamanca) ● Norman F. Blake (University of Shefﬁ eld) ● Juan de la Cruz (University of Málaga) ● Bernd Dietz (University of La Laguna) ● Angela Downing (University of Madrid, Compluten se) ● Francisco Fernández (University of Valen cia) ● Fernando Galván (University of Alcalá) ● Francisco García Tortosa (University