NATURE BIOTECHNOLOGY VOLUME 25 NUMBER 11 NOVEMBER 2007 1191

Companies jostle for lead in RNAi, despite uncertainties

Commercial activity in the RNA interference (RNAi) space continues apace, even with key challenges related to interpretation of the technology, a wall of regulatory issues and several intellectual property (IP) contests remaining.

In early September, Alnylam Pharmaceuticals, of Cambridge, Massachusetts, teamed with Isis Pharmaceuticals, of Carlsbad, California, in a joint venture called Regulus Therapeutics in Carlsbad, California, which will explore microRNA (miRNA), touted as likely to yield the next generation of RNA therapeutics. About a dozen days later, Alnylam severed ties with partner Merck, of Whitehouse Station, New Jersey, a divorce that had been precipitated when Merck bought Alnylam’s rival Sirna Therapeutics for $1.1 billion last year. And thus the field of research that started as a trot has begun to sprint.

“Just about every month, we see new [RNAi] market entrants,” notes Alan Sachs, vice president of RNA therapeutics for Merck Research Laboratories. Sachs says the Sirna buyout “complemented our existing capabili-ties and allowed us to take RNAi technology to the next level—the clinic.”

Sirna’s phase 2 product, Sirna-027, for age-related macular degeneration, is part-nered with Allergan, of Irvine, California. Alnylam had reached that stage, too, with its front-running product, ALN-RSV01, which is in phase 2 trials for respiratory syncytial virus infection. There are a host of firms now working in the space, but observers suggest Alnylam and Sirna sit at the top of the RNAi heap (Table 1).

Alnylam’s work has garnered deals with Novartis, which took a nearly 20% stake of the company, and Basel-based Roche bought a 5% stake as part of a deal for cancer drugs. Although Merck signed a collaboration with Alnylam in 2003, the pharma firm acquired Sirna to give itself “the opportunity to use RNAi to target genes in a variety of diseases, greatly expanding the number of druggable disease targets and potentially streamlin-ing drug development,” Sachs says. Merck aims to use Sirna’s technology “across all of

the therapeutic areas in which Merck does research” and did not believe it would be able to do so “within the confines” of its Alnylam deal. As such, the companies went their sepa-rate ways.

Although pharma’s whopper bets on RNAi drugs continue—London-based AstraZeneca signed a potential £200 ($407) million licens-

ing agreement this year with Silence Therapeutics, of London, for respiratory-disease targets—successful commercialization faces several challenges, the key hurdle being delivery. It’s possible to get the drug into some solid tumors and organs such as the liver and the eyes, but safety and selectivity “are two major challenges that still need

to be overcome,” says Sachs.Another potential problem is toxicity. Work

published last year by Mark Kay at Stanford (Nature 441, 537–541, 2006) found that lev-els of short hairpin RNA (shRNA) delivered by way of gene therapy that saturate the endogenous miRNA machinery killed half of 50 mice in an experiment. Alnylam scien-tists claim to have found a way around the problem in a paper in the October 11 issue of Nature (449, 745–747, 2007) by mediat-ing shRNAs’ effect downstream of miRNA biogenesis (unlike DNA-expressed shRNAs as used in Kay’s experiments).

Even if the technical hurdles can be sur-mounted, the FDA “is treating this whole area as a new discipline,” and thus with scru-tiny, cautions William Carter, chairman and CEO of Philadelphia-based Hemispherx Biopharma, which currently has Ampligen, a double-stranded RNA compound for chronic fatigue syndrome, under review. “They’re lumping together interference drugs with activator drugs in the RNA class.”

“There are a lot of issues when you deal with RNA, potentially,” Carter says. “Are you getting an unintended action, for example, or are you affecting some immunological cascade that you didn’t intend to look at?” Coagulation is troubling Isis in its antisense research, he says. “We have had to do a lot of comparative analysis of our class of RNA therapeutics with interference type RNAs, and we’ll be publishing some of that in the foreseeable future,” Carter says.

“Just about every month, we see new [RNAi] market entrants,” notes Alan Sachs, vice president of RNA therapeutics for Merck Research Laboratories.

NEWS©

2007

Nat

ure

Pub

lishi

ng G

roup

ht

tp://

ww

w.n

atur

e.co

m/n

atur

ebio

tech

nolo

gy

1192 VOLUME 25 NUMBER 11 NOVEMBER 2007 NATURE BIOTECHNOLOGY

Success with miRNA seems further off. Rather than encoding proteins, about 500 known miRNAs control the expression of up to one-third of all human genes. In vivo experiments suggest that antagonizing mutated miRNA targets may correct more than a single disease target, and could fix an entire disease pathway. Andrew Fein, ana-lyst with C.E. Unterberg, Towbin, in New York, predicted that miRNAs will become “the oligonucleotide candidates of choice in developing viable drug candidates,” and encouraged investors to view Rosetta Genomics, of Rehovot, Israel, and Regulus “in the same light as Sirna and Alnylam were viewed in 2003.”

Merck is working in the miRNA space—a Nature paper (447, 1130–1134, 2007) pub-lished in June describes a functional relation-ship between the tumor suppressor protein p53 and miR34. But Sachs regards miRNA as even more nascent than RNAi, com-menting that “much more work needs to be done to gain a better understanding of its potential.”

Table 1 Selected firms in RNA researchCompany (location) Technology Product, stage

Alnylam RNAi ALN-RSV01, phase 2 for respiratory syncytial virus

Sirna RNAi Sirna-027, for age-related wet macular degeneration (AMD). (Now called AGN211745, partnered with Allergan in phase 2)

Regulus miRNA Therapeutic targeting miR-122 for treating hepatitis C, preclinical

Quark Biotecha

(Fremont, California)

siRNA RTP801i-14, phase 1/2 in wet AMD

Silenceb RNAi Atu027, preclinical

Opko Healthc

(Miami, Florida)

RNAi Bevasiranib, phase 3 in wet AMD

Isis Antisense Vitravene (fomivirsen), approved for cytomegalovirus

Benitec

(Melbourne, Australia)

DNA-directed RNAi (ddRNAi), short hairpin RNAs (shRNA)

Phase 1 product targeting HIV/AIDS

Calando Pharmaceuticals

(Pasadena, California)

RNAi CALAA-01, formulated with firm’s RNA/oligonucle-otide nanoparticle delivery (RONDEL) technology, is preparing for phase 1

CytRxd

(Los Angeles, California)

RNAi Preclinical

Tacere Therapeutics

(San Jose, California)

Short hairpin RNAs (shRNA)e

TT-033, preclinical, hepatitis C

Rosetta Genomics miRNA Hopes to launch three miRNA diagnostic products in 2008

Hemispherx RNA Ampligen, double-stranded RNA compound, under review

aPartnered with Pfizer, of New York. Quark acquired product from Silence. bFormerly Atugen. cFormed through merger of Acuity Pharmaceuticals, Froptix and eXegenics. dCytrx contributed its RNAi assets to RXi Pharmaceuticals, and owns 85% of the firm. eLicensed from Benitec.

Meanwhile, the probable IP clashes between Merck/Sirna and Alnylam will be made more confusing thanks to the tightening in April of the “non-obviousness” requirement in patent applications, says Kevin Buckley, partner in the St. Louis-based Biotactica law firm, which specializes in the life sciences.

“The hurdle now [to get a patent issued] is to prove some kind of heightened, unex-pected utility, some surprising use, which is going to be hard to do,” he said. “It’s going to be much harder for any patent attorney to suggest that something that is already known, like a small interfering RNA, has some non-obvious use.”

Verbal guidance from the US Patent and Trademark Office suggests patent seekers will need to perform gene-walking studies to prove nonobvious features—a require-ment that puts the squeeze on universities and small startups. “It’s not part of a venture capitalist’s model to spend money on preclin-ical work before you can even file a patent application,” he notes.

Randall Osborne, Mill Valley, California

NEWS©

2007

Nat

ure

Pub

lishi

ng G

roup

ht

tp://

ww

w.n

atur

e.co

m/n

atur

ebio

tech

nolo

gy