Neil P. Desai, PhD Vice President, Research and Development Abraxis BioScience, Inc

1. Nanoparticle albumin bound (nab) technology : A nanotechnology platform for biologically interactive drug delivery and targeting Neil P. Desai, PhD Vice President, Research and Development Abraxis BioScience, Inc

2. Nanoparticle Albumin-bound (nab) platform technology Albumin cryo-TEM Active drug in nanoparticle is in non-crystalline, amorphous, readilybioavailable state Mean size = 50-150 nm Concentration dependent dissociation into individual drug-bound albumin molecules Hydrophobic drugs, e.g.,Paclitaxel, docetaxel, rapamycin etc.

3. Taxol Abraxane Abraxane (nab-paclitaxel) is a solvent-free ‘nano’ version of Taxol (cremophor-based paclitaxel) Abraxane received FDA Approval January, 2005 for metastatic breast cancer Contents: Paclitaxel 6 mg/ml Cremophor 537 mg/ml Ethanol 396 mg/ml Contents: 100 mg paclitaxel 900 mg albumin No Surfactants/Solvents

4. Abraxane approved by FDA with about twice the response rate of Taxol in metastatic breast cancer Source: Abraxane Package Insert

5. Negatively Charged Albumin - - - - - - - - - - - - - - - A key aspect of nanoparticle stability of nab-paclitaxel is size and zeta potential Negatively charged nanoparticles resist agglomeration Reproducible, narrow size distribution by Laser Light Scattering Mean Particle Diameter ~ 130 nm • nab nanoparticles are physically stable for several days in suspension

6. Rapid disintegration of nanoparticle Concentration above which nanoparticles remain intact and stable Mean Cmax for 260mg/m2 Paclitaxel Concentration in Plasma (ug/ml) Nanoparticle Release of nab-paclitaxel in simulated plasma measured by Laser Light Scattering • From a nanoparticle size of ~ 130 nm, there is rapid dissociation upon dilution in plasma into complexes in the 10 nm size range

7. Gp60 Receptor Caveolae SPARC Nab-platform utilizes endogenous albumin pathways of endothelial transcytosis (gp60) and intratumoral binding of SPARC Albumin-Bound Drug Albumin-Drug Accumulation

8. Rapid Tumor Accumulation of nab-paclitaxel in tumor Fluorescent nab-paclitaxel Nanoparticles* in Syringe injected via tail vein 1 min after I.V. injection Imaged Tumor MOUSE TUMOR MODEL Imaging under Hg-lamp with 500-550 nm bandpass excitation; *nab-paclitaxel containing 0.3% Fluorescent Marker 15 min after I.V. injection • 33% higher tumor accumulation of paclitaxel over 24 hr confirmed with radiolabelled nab-paclitaxel as compared to Taxol (p<0.0001) ABI, data on file and Desai N, et al. Clin Cancer Res 2006;12(4), 1317-24

9. Comparing ‘nano’ paclitaxel vs standard paclitaxel • Close and extensive interaction with FDA over almost 10 years leading to approval of Abraxane • Extensive preclinical testing program comparing Abraxane and Taxol • Intravenous toxicology in multiple organ systems • Biodistribution • Metabolism • Excretion • Reproductive toxicology in males and females • Tumor efficacy studies • Mechanistic studies elucidating pathways of drug transport • Other studies… • More than 1000 patients in carefully controlled clinical trials; more than 20000 patients treated since approval • No new or unique toxicities seen with Abraxane that are different from conventional paclitaxel (Taxol) • We believe the FDA has adequate procedures in place to regulate nanotechnology based drugs

10. Definitions of Nanotechnology adopted by FDA • FDA has not established its own formal definition ..Our understanding is that the FDA currently relies on the NNI definition. • National Nanotechnology Initiative (NNI): • Nanotechnology is the understanding and control of matter at dimensions of roughly 1 to 100 nanometers, where unique phenomena enable novel applications. …. At the nanoscale, the physical, chemical, and biological properties of materials differ in fundamental and valuable ways from the properties of individual atoms and molecules or bulk matter. • NCI Cancer Nanotechnology Plan (July 2004): • Nanotechnology refers to the interactions of cellular and molecular components and engineered materials - typically clusters of atoms, molecules, and molecular fragments - at the most elemental level of biology. Such nanoscale objects - typically, though not exclusively, with dimensions smaller than 100 nanometers - can be useful by themselves or as part of larger devices containing multiple nanoscale objects.

11. Nanotechnology / drug-delivery literature review: Is the 100 nm cutoff appropriate?Search: Pubmed/Internet [keywords: nanoparticle AND size AND drug AND delivery] • 446 abstracts found (1990 – 2006) • 152 abstracts provided nanoparticle size information in range of 1-1000 nm (96% from academia, only 4% from industry) • Majority, almost 80%, describe nanoparticles > 100 nm % Distribution of publications with reference to nanoparticle size

12. Meeting current definitions of Nanotechnology : Other nab products in development nab-rapamycin nab-17AAG nab-5404 Do these products, all produced by nab-technology, sharing similar physicohemical and biological properties, meet the current NNI size definition ?? nab-17AAG nab-5404 nab-rapamycin Mean Particle Diameter ~ 89 nm < 100 nm Mean Particle Diameter : 88 nm < 100 nm Mean Particle Diameter : 113 nm >100 nm Yes Yes No

13. Recommendations for revising current definitions of size range/function for nanotechnology drug products • Function: • Must provide special characteristics – e.g., novel physical characteristics, unique delivery, cellular penetration, receptor binding, targeting etc. • Suggested size cutoff equivalent to pore size of sterile filter (220 nm) : • 220 nm or 0.22 um is relevant size cutoff for sterile filtration to ensure that injectable pharmaceutical nanotechnology products are sterile • Below about 220 nm, we are outside the visible range of an optical microscope and special techniques are required to characterize these structures. • Establish a committee to determine cut off size for nanotechnology definition