PolyActive™ A biodegradable polymer-based drug delivery system

PRODUCTS DRUG DELIVERY FACTSHEET PolyActiveTM A biodegradable polymer-based drug delivery system­ CONTRACT DEVELOPMENT PHARMACEUTICAL INNOVATORS PRODUCTS DRUG DELIVERY CONTRACT DEVELOPMENT PolyActive PolyActive is a biodegradable polymeric drug delivery system. Its biodegradability­, extensive safety record and linear­ release properties make PolyActive an excellent technology for the controlled release of proteins and lipophilic small molecules. Products based on PolyActive can be used for both local and systemic ­ ad­ministration­, and have applications in pharmaceutics and medical technology. PolyActive composition PolyActive represents a series of poly(ether ester) multiblock copolymers, based on poly(ethylene glycol), PEG, and poly(butylene terephthalate), PBT (Figure 1). A major advantage of this system is the ability to vary the amount and length of each of the two building blocks, creating a diverse family of customized polymers. Polymer matrix characteristics such as rate of controlled release, degradation, swelling and strength can be precisely controlled by the appropriate combination of the two copolymer segments. Key attributes of the PolyActive drug delivery system: + Suitable to encapsulate both small- and macromolecules Degradation of PolyActive PolyActive degradation occurs by hydrolysis of ester bonds and oxidation of ether bonds. The rate of degradation depends on the selected polymer composition: polymers with higher PEG content show a faster degradation profile. In addition, the configuration of the PolyActive product also impacts the degradation rate; e.g. microspheres, in general, degrade faster than dense cylinders (Table 1). Table 1 Configuration Example of delivery product + Controllable, including linear, release profiles + Low initial release: no burst + Strong in vitro – in vivo correlation­ + Well-preserved compound stability­ and activity + Biodegradable and biocompatible­ + Systemic and local applications + Extensive biological safety file + FDA approval and CE mark for medical devices + Patent protected Example of active compound Microspheres Parenteral delivery systems Biotherapeutics Films Topical delivery systems Growth factors, anti-infectives Gels/Wafers Local drug delivery system Oncolytics Rods Removable delivery systems Psychotropics, contraceptives Coatings Implant coating delivery systems Anti-proliferative agents PolyActive applications Using PolyActive allows the development of burst-free drug delivery systems, and its hydrophilic nature conserves the stability of labile bio­pharmaceuticals, such as proteins. Products made from PolyActive can be processed into various shapes and configurations, thereby allowing them to be used in a wide range of applications. Performance Release rates from PolyActive can be tightly controlled. Adjusting the copolymer composition gives control over both the diffusive and degradation properties of the polymer, allowing control over the release rates of diverse molecules. Figure 1 PolyActive molecular structure Biodegradable multiblock copolymers 2 building blocks hydrophilic aPEGTbPBTc a= PEG MW b= PEGT weight % hydrophobic c= PBT weight % References 1 Bezemer J.M. et al., J. Controlled Rel., 64: 179-192, 2000 2 Bezemer J.M. et al., J. Controlled Rel., 67: 233-248, 2000 In in vitro studies, a constant release of compounds has been achieved from PolyActive products without an initial burst effect, with release controllable from minutes to months (Figure 2). 600 500 3 Bezemer J.M. et al., J. Controlled Rel., 67: 249-260, 2000 4 patent US5980948 400 300 200 100 0 0 5 10 15 20 25 Excellent in vitro – in vivo correlation PolyActive release profiles show an excellent congruence between release in vitro in PBS and in vivo in rats. With the use of PLGA-based microspheres, in vitro and in vivo release profiles may differ considerably. In contrast to PLGAbased microspheres, protein diffusion through the PolyActive hydrogel is the main rate-controlling factor, and this process progresses similarly in vitro and in vivo. This induces an excellent in vitro-in vivo correlation. Time (days) Figure 3. Activity of lysozyme released from two different PolyActive films. Molecular weight of the PEG segment is 1000 g/mole, and PEG/PBT ratio is 60/40 (I) and 40/60 (O). Preserved stability of the encapsulated compound A key issue in the design of controlled release systems for biopharmaceuticals, and in particular proteins, is the integrity of the encapsulated compound. Due to the presence of hydrophilic poly(ethylene glycol) segments, PolyActive exhibits a hydrogel character, providing a natural environment for compounds such as proteins. Unlike PLGA, degradation products of PolyActive do not create an acidic environment. An acidic environment may cause the released protein to lose its activity. PolyActive preserves the activity and stability of the embedded compound. Assessment of the activity of a model protein (lysozyme) after release from PolyActive shows that the PolyActive matrix and production process have no adverse effects on protein activity (Figure 3). This is a considerable benefit compared to PLGA-based systems which have shown an extensive reduction of lysozyme activity. The preservation of biological activity after release from PolyActive has been demonstrated both in vitro and in vivo with other therapeutically relevant proteins and peptides (Table 2). 120 100 80 60 Salmon calcitonin IFN alpha 2b rhGH 3.4 20 21 + + + + + + TGF beta RhEPO rhBMP2 IgG antibody 25 35 36 160 + + + + + + + - 14 17 29 67 + + + + + - Model proteins Lysozyme Myoglobin Carbonic anhydrase BSA (albumin) Figure 4. Pharmacokinetics of single dose Locteron 16 Locteron 20 µg 14 Locteron 80 µg 12 Locteron 320 µg 10 8 6 4 2 0 40 20 0 in vitro in vivo Size data data Compounds (kDa) available available 18 PolyActive manufacturing PolyActive microspheres, suitable for preclinical and clinical evaluation, can be produced under cGMP conditions in OctoPlus’ pilot plant in Leiden, the Netherlands. PolyActive is manufactured under a supply agreement on 10-20 kilogram scale under GMP conditions. Polymers containing 30-90 weight percent soft segment and PEG-blocks with molecular weights varying from 300-10,000 g/mole are currently available. Lysozyme activity % Table 2: OctoPlus has evaluated different therapeutic peptides and proteins in combination with PolyActive. IFNa (pg/ml) Cumulative alfa interferon release (µg) Figure 2. Controlled release of alfa interferon from PolyActive microspheres. 0 10 20 30 40 Time (days) Application of PolyActive in human pharmacotherapy OctoPlus uses PolyActive to develop its controlled-release alfa interferon product LocteronTM. Locteron combines PolyActive microspheres with BLX883, a recombinant alfa interferon produced by OctoPlus’ co-development partner Biolex Therapeutics in its patented LEX SystemSM. Figure 4 shows plasma levels of alfa interferon after subcutaneous injection of Locteron in humans. The graph shows that the release from the PolyActive microspheres does not induce a so-called burst effect and is gradual during approximately two weeks. For more information on Locteron, please refer to our Locteron Factsheet. Similar results have been obtained with other pharmaceutical proteins in animal studies. Table 2 shows several compounds evaluated in combination with PolyActive Safety and clinical data In addition to over a decade of successful in vitro toxicity and biocompatibility assays, PolyActive has been used in implants in more than 5,000 patients and in over 2,000 animals (rats, rabbits, dogs, goats). An extensive biological safety report is available for the technology, and FDA and CE approval have been granted for two implantable orthopedic medical devices made from PolyActive. Partner with OctoPlus for drug delivery with PolyActive OctoPlus is actively pursuing new partnerships to develop products based on the PolyActive delivery system. As a medium sized organisation, we are flexible in constructing partnership agreements and open to take on some of the risk and cost for the development of promising compounds. Our priority is to build successful long-term drug delivery partnerships. Please feel free to contact us and discuss your ideas. -5 0 5 10 15 20 25 Time (days) Person to contact Gerben Moolhuizen, Chief Business Officer OctoPlus N.V. Zernikedreef 12 2333 CL Leiden, the Netherlands Telephone +31(0)71 524 40 44 Fax +31(0)71 524 40 43 E-mail octoplus@octoplus.nl Website www.octoplus.nl Person to contact in the USA Michiel Lodder, Director Business Development OctoPlus Inc. 25 First Street, Suite 300 Cambridge, MA 02141, USA Telephone +1 617 225 2510 Fax +1 617 225 2481 E-mail octoplus@octoplus-inc.com Website www.octoplus-inc.com