The biotech's top asset is a unique RNAi technology platform dubbed Stealth RNA (rxRNA), featuring a 25-nucleotide length
and a penchant for avoiding the Dicer. Using special delivery systems, RXi is applying rxRNA to target genes linked to Lou
Gehrig's disease, high cholesterol, and obesity. The shop is also working on yeast-based delivery to the gut that could become
the first orally administered RNAi drug,
CEO Tod Woolf, a Sirna alum who codeveloped rxRNA, insists that systemic delivery will be solved, but in a novel way. "It
will not be like a small molecule that goes through the body—which is unfortunately what many people in Big Pharma see as
the standard. The delivery technology will be specific to the target tissue in the same way that RNAi is specific to the target
gene," says Woolf.
mdRNA, Inc. Another pure-play RNAi spin-off (from Nastech), mdRNA is developing its own RNAi trigger based on longer siRNAs—so-called
Dicer-substrate RNAs, or three-stranded siRNAs. CEO Michael French, who previously led Sirna through the Merck acquisition,
says, "If we all threw up our hands and said, 'OK, Alnylam or Sirna wins, and the only RNAi-based therapeutic that's going
to work is one with 19 to 21 base pairs,' I think we'd be doing society and medicine an injustice." mdRNA has preclinical
programs in influenza and inflammation.
Benitec This Australian pure-play is the leading maker of DNA-directed RNAi (ddRNAi), yet another alternative to the Tuschl siRNA.
Benitec is sponsoring one of the most ambitious RNAi clinical trials to date: a Phase I led by City of Hope's John Rossi for
AIDS-related lymphoma, in which RNAi-modified stem cells are transplanted into patients' bone marrow.
And more . . . Rossi, a low-profile RNAi research luminary, also co-founded Boston-based Dicerna last November to test the potential of his own approach, using long strands of siRNA and targeting an earlier stage in the
With systemic delivery the highest R&D hurdle, the RNAi space's fastest growing specialty is figuring out how to build microscopic
Trojan Horses for the RNAi trigger. The leader of the pack seems to be Vancouver's Tekmira (newly merged with cross-town Protiva), with its liposomal formulations. Other shops of interest include Seattle-based Targeted Genetics; Intradigm, a startup in San Francisco; Boston-based Cequent Pharmaceuticals; Mirius Bio in Madison, WI; and California's Calando.
Finally, Isis Pharmaceuticals is the granddaddy of the gene-silencing business. Launched in 1989 by RNA research pioneer Stanley Crooke, the Carlsbad,
CA, biotech is one of the few profitable antisense development shops.
Antisense drugs use a single (rather than double) RNA strand to target messenger RNA, and a less straightforward route than
the RNAi pathway. As a result, antisense lacks RNAi's exceptional potency and specificity. Isis succeeded in marketing one
antisense drug, Vitravene, for ocular injection against AIDS-related cytomegalovirus. But the antisense space has mostly gone
black due to a string of clinical defeats.
Accordingly, Crooke has undertaken a subtle rebranding. RNAi, he says, is merely a subset of antisense. "We've pioneered
all the major mechanisms in antisense, including, of course, RNAi." In any case, Isis has a second generation crop of candidates
in its pipeline for cancer and cardiovascular, metabolic, and inflammatory diseases; it boasts partnerships with J&J, Lilly,
Novartis, Merck, and Teva. But the headlines are its antisense cholesterol fighter, mipomersen, in Phase III, and the $1.5
billion milestone deal ($325 million up front plus 50 percent of profits) inked in January with Genzyme to develop and market
the apoB-100 inhibitor.