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Access Aims to Develop Oral Drug-Delivery Technology for RNAi Therapeutics

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By Doug Macron

Access Pharmaceuticals last week announced that it has begun an in-house effort to adapt its proprietary vitamin B12-based technology for therapeutic RNAi applications and potentially develop orally delivered drugs.

The technology, dubbed Cobalamin, is based on the body's natural vitamin B12 uptake mechanism, Access CEO Jeff Davis told RNAi News this week. It involves merging a polymer and active pharmaceutical ingredient to make a nanoparticle, which is then coated with the vitamin.

"We basically trick the body into thinking its absorbing vitamin B12," he said.

The company acquired Cobalamin a few years ago but it has been on the backburner following a corporate reorganization that shifted Access' focus onto oncology-related products, Davis explained. Looking to eke some value out of the technology, however, Access began investigating its potential to deliver macromolecules, namely insulin and human growth hormone.

"In our preclinical animal models [with insulin and HGH], we've shown that we can make this particle, coat it with vitamin B12, have the animals ingest it orally, and achieve high levels of oral bio-availability," he said.

The company's success delivering these two molecules led to a number of collaborations with pharmaceutical and biotech firms, which in turn triggered discussions about using the Cobalamin technology for siRNA delivery.

"Access scientists and collaborators have so far demonstrated in pre-clinical models that Cobalamin formulations are effective in achieving good oral drug delivery of charged peptides such as insulin and human growth hormone," David Nowotnik, Access senior vice president of research and development, said in a statement. "These successes with molecules which share some of the same physical characteristics as siRNA would indicate that we should now be able to generate effective formulations of Cobalamin nanoparticles for delivery of siRNA."

In addition, cells in diseased states, such as cancer cells, are "voracious consumers of vitamins including vitamin B12," suggesting that Cobalamin nanoparticles carrying an RNAi payload would have a natural targeting mechanism, Davis said.

Already, he added, Access has been in discussions with a number of big pharmas interested in the technology as a potential solution for RNAi drug delivery. "There is a lot of money being spent in [the RNAi] area right now, and people think it holds a lot of promise," he said. "Some large companies have already made big financial investments in the area, but there still seems to be a lot of concern about how to get these RNAi [molecules] into the cell."

In order to see if the Cobalamin technology can offer one solution to the delivery problem, Access is currently evaluating whether the approach can be used to achieve cellular uptake of an siRNA-loaded nanoparticle in vitro.

"Once we get a formulation we find is working well, then we'll take it into animal models," he said. "I think in four to six months we can figure out whether or not we can get [siRNAs] into the cell and have a fairly good idea of proof of concept."

While the initial focus is simply on getting the nanoparticles into cells, Davis said that Access envisions a situation where a Cobalamin-formulated RNAi drug could be delivered orally.

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"You could use vitamin B12 as a Trojan horse twice," he explained, first taking advantage of the gut's absorption of the vitamin to carry the nanoparticles through the digestive tract and into the bloodstream. Then, the particles would be absorbed by cells through natural vitamin B12-uptake mechanisms.

"So there are two opportunities" for the technology, Davis said. "The one that's most important for RNAi is [using it to get the gene-silencing agents] … absorbed into the cell. If we can do that, maybe we can do it twice, making it orally bio-available."

Should the Cobalamin technology prove effective for delivering RNAi molecules, Davis said that Access would likely look for a partner to handle its development.

"RNAi … is not what I'd characterize as core [focus] for Access," he said. "It's sort of serendipitous that we had this technology on the shelf, did a little work on [insulin and HGH], and were able to find collaborators" for those programs.

"If someone said, 'Do you want to spin the [RNAi] technology out or sell it off,' I think we'd be amenable to that at this stage," he added. "We don't have aspirations of becoming … a fully integrated pharmaceutical company, so [when it comes to deals] we're fairly flexible."

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