A Versatile Nano and Micro Carrier for the Delivery of Native Proteins*

Medusa®, a self-assembled poly-aminoacid nanogel system, is a versatile protein carrier for the development of novel and second-generation long-acting native protein drugs.

Flamel’s Unique Method for the Controlled Release of Proteins and Peptides

There is a large unmet therapeutic need (and corresponding market opportunity) for better drug delivery of proteins and peptides. While many of these drugs have demonstrated great success in treating patients, they have been limited in their application due to concerns about side effects resulting from the manner in which the drugs are released within the body.

The following graph presents the evolution of the delivery of proteins:

Among the different strategies (e.g., protein engineering, changes in primary structure, fusions, chemical modifications, glycosylation, pegylation, polymer conjugates), the approach of delivering native protein drugs is the most promising because it permits full release of active drugs.

Using its Medusa® nanogel, Flamel is developing second-generation formulations of native protein drugs with better performance (i.e. long time of action, high bioavailability and efficacy, reduced side effects and improved compliance) compared with first-generation proteins. We expect that the reduced side-effect profile will allow for increased dosage of some proteins, thus extending their efficacy and potential applications.

Description

Flamel's Medusa® polymer is made of glutamic acid, a naturally occurring aminoacid, and Vitamin E. The polymer is amphiphilic and spontaneously forms stable nanogel in water. Every nanoparticle consists of hydrophobic nanodomains rich in Vitamin E and hydrophilic polyglutamate that are exposed to water. They are robust over a wide range of pH values and can be stored as either stable liquid or stable dry forms that can be easily reconstituted in water.

The design of the Medusa® “polypeptide-like” aminoacid polymers allows a non-covalent capture and subsequent delivery of native peptide or protein drugs.



Once injected in the body, the nanogel releases the captured-drugs in a controlled manner and over an extended period of time. Both processes (capture and release) are non-denaturing, which preserves structural integrity - and hence the biological activity - of the drug. The transient non-covalent interactions dictate the pharmaco-kinetic profile (C_max and AUC, in particular) of the released drugs.

Performance

• The biological activity is maintained: no modification of the carried biologics.
• 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.

Advantages

• Non-denaturing formulation and delivery of native and fully active protein drugs;
  • This represents a competitive advantage over other, more deleterious approaches, e.g., protein engineering (changes in primary structure, fusions) or chemical modifications (glycosylation, pegylation and polymer conjugates).
• Fully biocompatible and biodegradable "polypeptide-like" aminoacid polymers;
• Medusa®’s nanogel is non-immunogenic and non-toxic, with no local irritation nor allergic reactions, as proven in human clinical trials;
• Cost effective process using mostly water (solvent- and surfactant-free); and,
• Strong intellectual property position (over 50 patents incl. US Patent N° 5,904,936 granted on May 18, 1999).

Collectively, Flamel’s Medusa® delivery system is a versatile nanotechnology which can accommodate the physico-chemical specifications and the delivery therapeutic-requirements of a wide variety of protein drugs. Medusa® nano-carrier is also suitable for the efficient delivery of insoluble (i.e., hydrophobic) small molecule drugs and could be applied to peptides

Medusa microparticles

Flamel Technologies has developed microparticles in order to increase the maximum injectable dose of protein or peptide by increasing the concentration of Medusa polymer (while maintaining a low viscosity).
The process of aggregation of the peptide/protein-loaded nanogel to form dense microparticles falls within Flamel's expertise and experience.
The microparticles allow a two step controlled release:
microparticle disaggregation followed by release from nanogel.
That approach is particularly adapted to hydrophilic proteins, peptides, and other large molecules.
This technology has been applied to formulate insulin, human growth hormone and several peptides.

Current Products Pipeline

Flamel's most advanced products are FT-105, a next-generation formulation of long-acting native insulin, IFN alpha-2b XL, a second-generation long-acting native interferon alpha-2b, and IL-2 XL, a second-generation long-acting interleukin-2 :

• FT-105 is Flamel's next generation basal insulin. Phase I results suggest that FT-105 has the potential to offer substantially better glucose control than currently-marketed long-acting insulins while providing true 24 hour coverage. Moreover, because FT-105 uses Flamel's MEDUSA technology, the recombinant insulin that patients receive is not denatured or chemically modified. A phase I glucose clamp trial was completed in September 2007.
  Please click here for top-line results of the Phase I study.
• IFN alpha-2b XL is a long-acting native interferon alpha-2b for the treatment of Hepatitis B and C and some cancers.
  On April 25, 2008, Flamel Technologies announced the presentation of results of two week study of interferon alpha XL at the European Association for the Study of the Liver.
  Click here to access the presentation entitled "Antiviral activity and tolerance of a novel interferon-alpha-2b sustained release(IFN-alpha-2bXL) compared to Peg-IFN-alpha-2b:a phase Ib trial in HCV patients".
  
• IL-2 XL, is a second-generation long-acting interleukin-2
  Flamel Technologies presented at the 2006 ASCO (American Society of Clinical Oncology) Annual meeting (June 2-6, 2006) the preliminary results of the phase I/II of its controlled-released formulation of interleukin-2 (IL-2 XL). Click here to access the document. .

Flamel has also proven in animal models the performances of Medusa® with two other protein drugs:

• hGH, a long-acting native human Growth Hormone for the treatment of growth disorders, and,
• IFN beta XL, a long-acting interferon beta for the treatment of multiple sclerosis (unavailable for licensing).

Flamel Technologies is exploring additional opportunities for the Medusa technology:

• Formulation and delivery of several active pharmaceutical ingredients (APIs): multiple peptides, immunmodulators, antibody fragments, full monoclonal antibodies and fusion proteins
• New Medusa cationic polymers allowing to formulate and deliver siRNA and DNA fragment
• Oral Delivery of peptide drugs through the combination of Micropump® and Medusa®.