“With multiple candidates in the clinic addressing a wide range of indications, data demonstrating the power of RNAi as a therapeutic modality are rapidly accumulating,” says Dr. Christopher Anzalone, Arrowhead’s CEO. “Having access to Axolab’s expertise in preclinical development complements Arrowhead’s capabilities well and provides us with yet another tool for preclinical and clinical collaborations in the field. Now, with the company’s already established intellectual property position and array of proprietary delivery technologies, including Dynamic PolyConjugates (DPC) and RONDEL, Arrowhead is uniquely positioned to build its own pipeline of RNAi therapeutics and provide partners entry to this promising area in a rapid and cost-effective manner.”  

 

Arrowhead has used a nontransgenic mouse model of chronic HBV infection of the liver to test the efficacy of its DPC technology for delivery of anti-HBV siRNAs. These mice produce HBsAg and HBV viral particles that are secreted into the blood. As a prelude to successful clinical development and commercialization, Arrowhead has secured a license granting it the exclusive right to develop, manufacture and commercialize siRNA therapeutics against the HBV genome to treat HBV from Alnylam Pharmaceuticals Inc.  

 

Alnylam President and Chief Operating Officer Barry Greene notes that there are three known modes for overcoming the delivery hurdles that have confronted RNAi therapeutics, liposome nanoparticles and chemistry conjugates (both Alnylam’s), and Arrowhead’s Dynamic PolyConjugates approach. In addition, there is Arrowhead’s RONDEL technology—new targeted, siRNA-containing therapeutics that employ a proprietary three-part RNAi/Oligonucleotide Nanoparticle Delivery (RONDEL) system, the foundation of which is a cyclodextrin-containing polymer.   

 

“Naked” siRNA is degraded and destroyed by nucleases in the bloodstream and is not taken up by cells, and also causes harmful immune reactions. The RONDEL system’s cyclodextrin-containing polymers protect the siRNA and allow it to reach its destination and perform its intended job; for example, to stop the runaway growth of tumor cells. Greene points out that RNAi represents a whole new class of therapies that have the near-term potential to transform a number of diseases. One he points to is TTR-mediated amyloidosis (ATTR), in which Alnylam is developing ALN-TTR, a systemically delivered RNAi therapeutic that targets the transthyretin (TTR) gene, to treat ATTR.  

 

ATTR is caused by mutations in the TTR gene, which is expressed predominantly in the liver, and results in the accumulation of pathogenic deposits of mutant and wild-type TTR protein in multiple extra-hepatic tissues, including the peripheral nervous system, heart, and the gastrointestinal tract.  

 

“As there are currently few options for patients suffering from this devastating disease, we aim to rapidly advance our ALN-TTR program and are committed to bringing this important medicine to ATTR patients in need,” he states.