Nucleic Acid Delivery

To date, the primary challenge to siRNA therapeutics has been delivering the fragile, often immunogenic and otherwise rapidly cleared siRNA molecules, into the cytoplasm of the cell, where RNAi activity occurs. To date, the hurdle of delivery has prevented siRNA therapeutics from reaching their full potential. Many companies have attempted to overcome the delivery challenge. Most early systems involved cholesterol conjugates or traditional liposomes. These have not yet proven optimal due to toxicity and immunogenicity when tested in human clinical trials.

To address the delivery challenge, Arrowhead has assembled a leading team of researchers with extensive siRNA therapeutic know how and one of the broadest portfolios of siRNA delivery technologies available, with the potential to unlock siRNA as a therapeutic class through superior delivery, including:

• The Dynamic Polyconjugate™ (DPC) system is an amphipathic polymer to which shielding agents such as polyethylene glycol, as well as targeting ligands are reversibly attached, thus protecting the fragile siRNA therapeutic and specifying tissue specific delivery.
• The RONDEL™ delivery system utilizes targeted cyclodextrin polymers to deliver siRNA and other oligonucleotides to tumors. Human in vivo gene knockdown has been demonstrated in a Phase I cancer trial, establishing proof of concept for the RONDEL system.
• Affiliate Leonardo Biosystems is developing a multi-stage delivery technology, initially for oncology applications. The first stage of the system consists of biodegradable silicon nanoparticles that are rationally designed to circumvent the multiple biological barriers en route to the target site. The first stage silicon particle is loaded with second stage delivery vectors such as liposomes or polymeric particles carrying a therapeutic agent, such as siRNA or a small molecule drug.
• Stable Nucleic Acid Lipid Nanoparticles (SNALP) through a license agreement with Tekmira.
• Roche's internally developed liposomal nanoparticles which have shown efficacy in vivo at knocking down targets in various animal disease models including models of human diseases such as cancer and chronic obstructive pulmonary disease (COPD).

No single method of delivery will be optimal for all disease areas, targets, and tissue types throughout the body. However, Arrowhead believes that these five technology platforms together represent the most comprehensive portfolio of solutions for effective delivery of therapeutic siRNA against a broad range of disease indications. We see this as transformational for Arrowhead and potentially for RNAi as a new therapeutic class of drugs. The ability to optimize delivery on a target-by-target basis is a critical tool, and we believe it positions Arrowhead as a powerful partner for biotech and pharmaceutical companies interested in developing candidates against multiple targets which may be "undruggable" by small molecule inhibitors or antibodies. We intend to use this leadership position to negotiate partnerships and collaborations as well as support our own internal pipeline of drug candidates.