By Doug Macron
Alnylam Pharmaceuticals' release of interim phase I data last week showing that its intravenous siRNA-based liver cancer drug could trigger an RNAi effect in humans when administered using Tekmira Pharmaceuticals' lipid nanoparticle technology marked a key milestone in overcoming the delivery challenge facing RNAi therapeutics (GSN 1/6/2011).
Tekmira President and CEO Mark Murray this week lauded the data as a confirmation that the company's technology "enables bona fide RNAi activity in man," and it added to the growing body of evidence supporting the overall use of lipid-based approaches for systemic RNAi drug delivery.
Still, some players in the field cautioned that the industry may be too focused on lipid delivery, potentially passing over other technologies that, while at an earlier stage of development, may ultimately be successful for certain indications.
"Clearly, the greatest advances [in the field] have been with lipids," Art Krieg, CSO of Pfizer's Research Technology Center, told Gene Silencing News recently. "With a technology like RNAi, as soon as you get something that works, there is a natural inclination to use that to start getting programs into the clinic.
"I think that's appropriate," he added. "You wouldn't want to … wait to get programs into the clinic until you solve every single delivery challenge there is. People are taking advantage of what they have now."
Stanford University's Mark Kay noted that "historically … lipid-based delivery systems are the ones that have been more well-studied and developed," and that there has been "good progress" in overcoming the toxicity seen when lipids and nucleic acids are complexed together.
At the same time, alternative approaches that appeared promising in culture ran into "a whole additional set of issues I don't think were well thought through before being tried," he said. "Some of the expectations of those were overstated based on very little data."
Nonetheless, Kay stressed that "until something works, I think it's important to pursue any approach that shows some sort of promise."
Johannes Fruehauf, vice president of research and development at Aura Biosciences and former vice president of Cequent Pharmaceuticals, said that over the past year, "there has been a bit of an awaking to … [the fact that] lipids have their inherent problems of manufacturing, stability, and certainly toxicity in many cases."
Turning an effective siRNA sequence into a drug "is not as easy as simply making a liposome," he said.
In addition to the significant work already conducted on lipids as drug-delivery vehicles, the "intense focus" on their use in therapeutic RNAi applications was due to a desire to crack systemic delivery, which would open the door to lucrative indications such as cancer and diabetes, Fruehauf added.
Those kinds of diseases, however, are "not where we will see the first clinical successes," he noted. "I'm sure the first clinical successes will be seen in the smaller indications that focus on local delivery to a more accessible organ."
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