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Silenced After All These Years

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If there’s anyone who can speak authoritatively about the use of RNA interference technology in the development of a therapeutic, it’s Sam Reich. As one of the founders and now executive vice president of research and development at Acuity Pharmaceuticals, Reich is part of the team to bring the very first siRNA to the US Food and Drug Administration for approval.

Acuity, which focuses on finding treatments for ophthalmic diseases such as age-related macular degeneration and diabetic retinopathy, was founded about four and a half years ago by scientists at the University of Pennsylvania’s Scheie Eye Institute. Reich was doing research at the time for his doctoral degree “looking for novel and better ways to target VEGF,” the gene known to be implicated in macular degeneration. “As ophthalmology researchers looking into … the biology of the retina and trying to find ways to inhibit VEGF, we basically made the discovery that we could exploit RNA interference,” Reich says.

Back in 2002, RNAi was still a mainstay of the research community and had not yet ventured into pharmaceutical development in any meaningful way. Reich and his fellow U Penn researchers were “very early in pioneering the concept” that RNAi could be useful in clinical settings, he says. The team did some of the earliest experiments with RNAi in mammalian cells and later in animal models, he adds. “A lot of this work was really the first translation of RNAi into a therapeutic application. We were first in phase 1, first in phase 2, first in humans.” Indeed, in the fall of 2004, Acuity became the first company to start phase 1 trials for Cand5, in which the first human was ever dosed with an RNAi-based therapeutic.

So it comes as no surprise to Reich that RNAi has become a tool of choice in pharmaceutical companies as well as in biotechs specifically built around the technology. “It’s something that works very, very well -- very predictably and very reproducibly,” he says. “We’re taking advantage of something the cell already does in order to have the desired outcome,” he adds, comparing RNAi-based drugs to the monoclonal antibody class that was also a successful way to mimic a natural process in the body.

Of course, being first to trials with a new technology means being first to FDA, and that’s rarely the situation a new biotech wants to be in. But Reich says the path has been relatively smooth. “When we first went before the FDA it was the first siRNA” to be presented as a therapeutic, he says. There were concerns on all sides as some academic papers pointed to a host of off-target effects demonstrated in the use of siRNAs, but Reich says that Acuity’s siRNA candidate sailed through safety testing and that the cautionary tales from academia didn’t turn out to be “a clinical reality.” He adds that FDA has treated them the same as any other candidate. “Seeing that safety and a battery of toxicity studies, [FDA] treats us as any other drug that’s safe,” Reich says.

Because Acuity’s candidate targets only the eye and can be delivered directly, the team found that there was “no systemic exposure,” Reich says. “It inhibits VEGF very potently in the eye, and nowhere else in the body.” That level of efficacy and specificity came as a surprise even to Acuity researchers when they first saw how cleanly the therapeutic delivered. “The safety advantages of this technology are one of the advantages that we wouldn’t have predicted four or five years ago -- that it actually would have safety advantages over older technologies,” Reich says.

Acuity’s lead candidate may have been the first siRNA to reach FDA, but several other companies aren’t far behind. “We’re quite confident that we’ll have the first approved siRNA,” says Reich, who believes this will be the first of many such therapeutics. “This is an important, novel class of compounds that will over time yield many drugs, and be a hugely important class of compounds for the biotechnology industry,” he says.

RNAi in Discovery and Development

The last several months have seen plenty of activity in the RNAi world, and much of that centered on work aimed at RNAi-based therapeutics. If you haven’t been keeping up with it, Genome Technology offers this cheat sheet to get you up to speed.

Last month, Alnylam Pharmaceuticals announced that it was presenting new preclinical data from its RNAi-based therapeutic program for the treatment of hypercholesterolemia, as well as from its collaborations in treatments for Huntington’s disease and neuropathic pain. The candidate for hypercholesterolemia may be furthest along, with Alnylam saying it plans to file an IND application for it this year. In testing on mice, in vivo systemic administration achieved silencing in about two days, according to data the company presented.

In other Alnylam updates, the company last fall entered into a partnership with Biogen Idec to develop RNAi-based therapeutics for PML, or progressive multifocal leukoencephalopathy, which is caused by a viral infection of the central nervous system.

Atugen, a subsidiary of SR Pharma, developed a promising RNAi candidate called RTP-801i, which it later licensed to Quark Biotech. Last month, the company announced that Quark was entering phase 1 trials with the candidate, which, like Acuity’s candidate, targets age-related macular degeneration. The start of the trial also triggered a $1.5 million milestone payment to Atugen.

In January, CytRx spun its three-year-old RNAi division out into a new entity called RXi Pharmaceuticals. RXi will start out with therapeutic areas that include oncology, neurodegenerative disease, obesity, and diabetes, according to the company. RXi hit the ground running, having been granted an siRNA candidate from CytRx linked to fat burning. The company will also carry on CytRx’s work in ALS with partners at Massachusetts General Hospital and the University of Massachusetts Medical School.

In late 2006, Chiang Li at the Beth Israel Deaconess Medical Center founded Cequent Pharmaceuticals in Cambridge, Mass. The company is based on a new concept called trans-kingdom RNAi, which designs potential drugs using non-pathogenic bacteria as a delivery tool for shRNAs. The company started with $6 million from a financing round that closed last November, and hopes to have its first new drug application filed in the first half of next year, according to CEO Peter Parker. Cequent’s first disease category is an inherited form of colorectal cancer.

At the end of last year, Nucleonics was dragged into the news when NIH’s Recombinant DNA Advisory Committee voiced concerns about the phase 1 clinical trial the company is planning for a hepatitis B therapeutic candidate. Reviewers thought the planned dosages were too high, and that preclinical trials should have included more than mouse testing. Nucleonics said it would consider and respond to the concerns, but added that it still planned to file an IND for the candidate in 2007.

Last fall, Merck announced that it would buy RNAi treatment company Sirna Therapeutics for $1.1 billion in cash. That acquisition was slated to close in the first quarter of this year. At the time, Merck officials noted that RNAi-based therapeutics were especially promising for cancer applications. Sirna’s lead candidate, which was at the time of the acquisition moving into phase 2 clinical trials, is aimed at patients with age-related macular degeneration. Sirna also has ongoing programs, both internally and externally, focusing on respiratory and infectious diseases, as well as therapeutic areas in metabolism, central nervous sytem, and dermatology.

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