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Arrowhead Research Demonstrates Successful "Silencing" of Widely Recognized Cancer Gene via RNAi in Humans

Published on March 22, 2010 at 6:30 AM

Arrowhead Research Corporation (NASDAQ: ARWR) today announced that the clinical trial being conducted by majority-owned subsidiary, Calando Pharmaceuticals, Inc. has demonstrated systemic delivery of siRNA and the successful "silencing" of a widely recognized cancer gene via RNA interference (RNAi) in humans. This represents a breakthrough for Calando, its proprietary RONDEL™ delivery system, and the field of RNAi.

It is thought to be the first ever demonstration in humans of targeted siRNA-containing nanoparticle delivery to tumors using systemic administration, delivery of functional siRNAs, and achievement of specific mRNA and protein reductions via RNAi. Thus far in the trial, no significant drug-related toxicities, known as serious adverse events (SAEs), have been observed that may limit use. Data based on Calando's study were published in the prestigious journal, Nature, on March 21, 2010 in an advance online edition. The article, titled, "Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles," can be viewed at: http://www.nature.com/nature/journal/vaop/ncurrent/full/nature08956.html. Further discussion of the article and the data may also be viewed at: http://www.nature.com/news/2010/100321/full/news.2010.138.html.

The study was led by Professor Mark E. Davis and a team of scientists at Caltech. It also included researchers and clinicians from UCLA and South Texas Accelerated Research Therapeutics (START), the two sites conducting Calando's clinical trial. The trial, which is investigating the safety and efficacy of drug candidate CALAA-01 and the broader RONDEL nanoparticle delivery system, represented the first time siRNA was systemically administered using a delivery system and the first use of siRNA against cancer in humans. CALAA-01 and the RONDEL™ delivery system widened their lead in the siRNA delivery field with the newly published data, which include:

  • Detection of RONDEL siRNA nanoparticles inside cells biopsied from tumors, demonstrating that RONDEL is capable of shuttling siRNA into tumors after being infused into the bloodstream of patients;
  • Presence of RONDEL inside tumors in a dose-dependent manner, meaning that the higher a dose administered to a patient, the higher number of nanoparticles reach the intended target;
  • Specific reduction in target mRNA (often referred to as "mRNA knockdown") encoding for the M2 subunit of ribonuceotide reductase (RRM2), a widely-recognized cancer target that CALAA-01 is engineered to decrease;
  • Specific reduction in target RRM2 protein levels (often referred to as "protein knockdown");
  • Indication that the mRNA and protein knockdown are mediated by delivered siRNAs and the RNAi mechanism as evidenced by accepted 5'-RACE analysis, proving that RONDEL is capable of enabling RNAi in humans.

For the past decade, the field of RNAi therapeutics has been the focus of much investigational effort and investment. RNAi as a platform is widely considered a potentially revolutionary new way of treating a wide array of diverse diseases, including many conditions that are currently considered "undruggable". It is an extremely powerful therapeutic tool because the production of any protein can potentially be "turned down" in a very specific way. As a result, investment in RNAi therapeutics has been widespread and is a major focus by most large pharmaceutical companies. However, the promise of RNAi as a new therapeutic class has not yet been realized. This has been, in large part, due to the lack of an effective and safe system for delivering highly fragile siRNA to intended tissues and cells. With its deep expertise and long experience in drug delivery technology, Calando recognized this opportunity to create significant value, and the current data suggest that it has capitalized on that opportunity.

"This breakthrough evidence provides important validation for siRNA-based therapeutics in general, as well as for our proprietary RONDEL delivery system, and for our lead siRNA therapeutic candidate, CALAA-01," said Dr. Christopher Anzalone, CEO of Arrowhead. "We congratulate the investigational team for their exceptional work and are gratified that our many years of support and investment in this technology have made this moment in medical history possible. We believe we are nearing the time when siRNA therapeutics can begin to make a historic leap from science to applied medicine, where it can truly make a difference as viable treatments for patients with a variety of prevalent unmet medical needs.

"These important proof-of-concept data position us well as we look to the next phase of Calando's development. Effective systemic delivery of siRNA has been referred to as the Holy Grail of RNAi therapeutics, and we have now shown that we can accomplish this in humans. We have always believed that great value would be created by the first company to demonstrate the following in humans: (1) siRNA delivery vehicles inside tumor cells; (2) target mRNA knockdown; (3) target protein knockdown; and (4) evidence that effects were mediated by the RNAi mechanism. We have now shown these, so we continue to see Calando as an attractive candidate for partnering and licensing opportunities both with respect to CALAA-01 as a specific drug candidate, as well as with RONDEL as a broad, flexible siRNA delivery system for delivering virtually any other oncology-related siRNA sequence. We are now focused on treating more patients at both UCLA and START. Importantly, we are not seeing drug-related SAEs, so while we have entered a dose range capable of triggering RNAi, we believe we are still far from a maximum tolerated dose (MTD). We intend to continue to escalate doses in search of that MTD." Dr. Anzalone concluded.

Calando's RONDEL siRNA delivery platform is designed to self-assemble with any siRNA therapeutic and to easily incorporate many different targeting molecules, making the platform potentially applicable to many disease indications beyond cancer. Importantly, the sugar-based system has not shown the immune system activation caused by other lipid-based siRNA delivery systems in pre-clinical and clinical development.

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