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
- 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
"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.