RNA Revolutionaries

"This is a gift from heaven." So said MIT biologist Phillip Sharp, Nobel laureate and founder of Alnylam Pharmaceuticals, to The New York Times in 2003. Sharp was rhapsodizing about RNA interference, or RNAi, the swift and efficient way a cell protects itself by dispatching tiny snippets of RNA to silence harmful gene expression. Researchers at Harvard had just succeeded in using RNAi to "turn off" a worm's genes, one at a time, to identify which causes obesity. And given that the human RNAi pathway is very similar to a worm's, this was yet another in a series of fast affirmations of RNAi's therapeutic promise. While gene silencing (through approaches such as antisense) has so far proved dicey, and RNA research has so far yielded a decade's worth of failed drugs, RNAi is sparking visions of a revolutionary technology spitting out one new highly specific compound after another—almost as fast as the Human Genome Project can name disease targets.

Today, just five years since Sharp's pronouncement and only a decade since the discovery of RNAi, the first RNAi drug, Opko Health's controversial bevasiranib, for wet age-related macular degeneration (AMD), is enrolling Phase III, with a competitor or two right behind.Moreover, in these tough financial times, RNAi R&D shops are flush with cash. Kalorama Information estimates that the best case market for RNAi and other nucleic acid (NA) therapies is worth $210 billion, led by neurological diseases ($83 billion), cancer ($44 billion), and autoimmune diseases ($42 billion). Since 2005, leader of the pack Alnylam has inked milestone deals ranging from $700 million to more than $1 billion with Novartis, Roche, and Takeda, while Merck bought Sirna Therapeutics flat out for $1.1 billion.

Yet despite the enthusiasm, the "gift from heaven" remains largely an article of scientific faith. While direct delivery to the eye and the lungs has been achieved, systemic RNAi delivery (intravenous or subcutaneous, for example), which would open up RNAi for many more diseases, is far more challenging. (Significant progress has been made for systemic delivery to the liver, tumor tissues, and kidneys.) "RNAi will not be validated as a therapeutic until there is a market launch of a systemically delivered product," says Barbara Bolten, a Decision Resources biotech analyst. "If this milestone is achieved, there will be an explosion of interest and investment equal to what we see in biologics today."

The Science of Gene Silence

The discovery of RNA interference is the latest triumph in the resurgence of the RNA molecule as a focus of intense scientific interest. Kicked to the curb by the mid-century discovery of DNA, nondescript, single-stranded RNA was long viewed as subsidiary to its double-helix master, shuttling production orders to the cell's protein-making refineries. In this scenario, proteins, designed by the DNA, carry out most of a cell's function, including the on/off switch for genes. (For another view of recent RNA research, see "That Thing about RNA".)

"There's been a huge leap in our understanding of RNA," says Jim Niedel, a managing director at New Leaf Venture Partners and former chairman of Sirna Therapeutics. "Just about everything that DNA, enzymes, and proteins do, RNA was basically there first."

Biologists Craig Mello, of the University of Massachusetts, and Andrew Fire, of Stanford, discovered RNAi in 1998 while studying the worm genome. The simple, elegant process by which RNA blocks gene expression was gradually worked out: As double-stranded RNA (dsRNA) enters a cell, it is recognized by an enzyme dubbed Dicer, which chops the long strands into many smaller units, 20 to 25 nucleotides long, called small interfering RNAs (siRNAs). These siRNAs are the stars of the show. Like dsRNAs, they're two-stranded. In the cell, the strands are separated and the active strand is loaded into the Slicer complex which is then guided by the small RNA toward its target: a long strand of messenger RNA (mRNA) carrying coded information from DNA to the cell's protein-making mechanism.

In Love with Interference

When Slicer reaches the mRNA, the siRNA finds the sequence of nucleotides that is its exact mirror opposite and binds to it—a perfect but fatal fit. For then Slicer, still attached to the siRNA, cuts the long mRNA in half. No longer intact, the mRNA appears to the cell as alien—and is pulverized. No messenger, no message, no protein. As aberrant protein function accounts for most diseases, interfering with such protein expression is predicted to have a therapeutic benefit.

Mello and Fire's eureka spurred a flurry of efforts to engineer the process to target specific genes. In a sign of delivery challenges awaiting them, researchers repeatedly met with failure, as the process triggered immune defenses that destroyed the RNA. Then in 2001, Thomas Tuschl, at Germany's Max Plank Institute, along with colleagues at MIT, UMass, and Harvard, hit upon the idea of making smaller siRNA triggers. At 20 or so nucleotides in length, the molecule hit all its marks.

Drug R&D couldn't be more efficient, at least on paper: ID a gene target and its nucleotide sequence (which will carry the information for the target messenger RNA), and then create a strand of RNA in the reverse order to trigger the process.

Alnylam's and Sirna's Quick Billions

Big Pharma and academia rushed to exploit RNAi's research prowess to accelerate discovery and validation of new drugs, while biotech rushed to place bets on its promise of breakthrough medicines. The first startup, Boston-based Alnylam, had access to co-founder Tuschl's intellectual property, and quickly consolidated its hold on fundamental RNAi patents. Among the large-caps, Novartis, Abbott, and Merck were first to come knocking, forming modest alliances.

Meanwhile, biotechs already working in RNA therapeutics leveraged their patents and expertise. In 2003, a San Francisco-based company that had had little luck turning out ribozyme drugs changed its name to Sirna Therapeutics, and its focus to RNA interference. Loading up on both venture capital and Big Pharma alliances, Sirna was soon nipping at Alnylam's heels.

"At the time, Sirna was a chemistry-based company, while Alnylam's strength was in biology," says New Leaf's Jim Niedel. "In 2003, when we were looking to invest, we chose Sirna because we thought that the issue of delivery would be best addressed by chemical modifications of the RNAi molecule."

In 2005, Novartis made a bold foray by signing a research alliance with Alnylam for more than $50 million in up-front payments (including the purchase of a 20 percent stake in the company), and a total potential deal valued at $700 million—what Alnylam's COO, Barry Greene, called "a game-changing event" for the biotech. "The Novartis deal was a significant turning point," says Barbara Bolten. "It was seen by the rest of the industry as validating Alnylam's approach to RNAi."

With 2006 came even more game-changing events. In August, GlaxoSmithKlein placed major chips on Sirna, signing a $700 million milestone deal to develop respiratory drugs. In October, Mello, then 45, and Fire, then 47, were awarded the Nobel Prize in Medicine for their discovery of RNA interference. Four weeks later, Merck won a bidding war to buy Sirna, ponying up a stunning $1.1 billion.

Sirna's stock value doubled overnight; analysts were doubled over in shock. "I don't think anyone saw it coming," Leerink Swann analyst William Tanner told MSNBC. "Big pharmaceutical companies tend to buy biotechnology companies with nearer term prospects."

More billion-dollar milestone deals have followed, and heavy up-front layouts are increasingly the rule. Last year, Roche signed with Alnylam for $331 million up front, and up to $1 billion in potential milestones to develop RNAi drugs for oncology and liver, respiratory, and metabolic diseases. In July, Takeda offered Alnylam $100 million in cash and more than $1 billion in milestones for drugs for oncology and metabolic disorders. Japan's largest drugmaker also won rights to market future Alnylam products in Asia—excluding the company's most advanced drug candidate, a phase II treatment for lung infections caused by RSV.

The Element of Risk

That the Roche and Takeda blockbuster deals were non-exclusive only confirmed skeptics in their view that the shopping spree said less about RNAi's value than it did about Big Pharma's desperation. Comparing it to the 1990s "genomics frenzy," "In the Pipeline" blogger Derek Lowe took aim at "[every large-cap's] very real fear of being left behind when a rare landscape-altering technology is potentially coming on."

The notion of a Big Pharma frenzy over an over hyped technology leaves RNAi insiders scoffing. "The details of the deals make it very clear that the Big Pharmas have done a careful risk assessment—and they're paying the amount of money that is reasonable," says Dirk Haussecker, a researcher, consultant and blogger at rnaitherapeutics.com (see "In Love with Interference".)

Exactly how risky is the technology? "The drug development risk essentially comes down to the choice of the right target, not the formulation of RNAi trigger," Haussecker says. While the drug-into-body problem looms, once safe and effective delivery technologies with appropriate pharmacologies have been developed for the various organs and cell types, these can be applied to a whole range of targets. A because the approach uses a cell's innate mechanism, relatively small doses have high potency. Nature made the approach very specific: the siRNA's patterned nucleotides are an exact fit with the target mRNA.

Screening for a potential siRNA to target a specific gene takes a matter of weeks, potentially shaving months or years off conventional drug discovery. And while small-molecule drugs and monoclonal antibodies largely been developed for a limited number of pathways, with many companies competing for the same target, the number of gene targets for RNAi is vast.

The Serious Contenders

The dynamic of the RNAi business today turns on IP—in particular, Alnylam's IP. Some RNAi shops therefore license rights to pursue siRNA drugs, others believe that by coming up with their own version of the RNAi trigger—using longer strands or unique chemical modifications—they may be able to operate independently of Alnylam's IP. However, the record suggests that Big Pharma partners do not necessarily share that view.

Alnylam is the only pure-play shop sporting a "Not for Sale" sign. Despite the soaring prices RNAi deals command, the biggest check the next decade will write is a reality check, and unproductive biotechs will go under. For the rest, survival will depend on partnerships or mergers with Big Pharma—or on striking gold in the clinic.

Here's the A-List of RNAi companies with a clear shot at survival:

Alnylam Pharmaceuticals The self-described RNAi patent gatekeeper is the 800-pound gorilla in this ring. Given the biotech's plans to pursue its own sales and marketing, its development strategy is to focus on diseases treated by specialists. "We're focused on target genes that are approachable from a delivery standpoint, and where the clinical validation is high," says CEO John Maraganore, a veteran of Millennium and Biogen Idec.

Alnylam has three leading drug candidates: ALN-RSV01, for RSV, direct delivery via inhalation, currently in Phase II; ALN-PCS01, targeting the PCSK9 gene for high cholesterol, systemic delivery to the liver via IV injection, pre-IND; and ALN-VSP01, targeting both the VEGF pathway and the KSP protein for liver cancer, pre-IND. "Behind these programs, we're pursuing Huntington's Disease, hepatitis C, PML, and pandemic flu," Maraganore says.

Alnylam has also launched Alnylam Biodefense, a public-private partnership to develop RNAi therapeutics against Ebola virus and other potential threats.

Sirna/Merck Rising out of the ashes of Ribozyme Pharmaceuticals, the San Francisco biotech capitalized on its nucleic acid technology and patents to become the first publicly traded RNAi company. In 2005, eyecare shop Allergan signed a codevelopment deal with Sirna for AGN-211745, targeting the VEGF1R gene for wet AMD via direct injection. In 2006, Glaxo inked its $700 million milestone deal for RSV and other respiratory targets. A few months later, Merck swept the biotech off its feet with its eye-popping $1.1 billion.

Alan Sachs, who took the reins after the acquisition, explains that unlike a hurry-a-product-to-market biotech, Merck has the deep pockets to take the time to "build a sustainable platform with the breadth to create best-in-class RNA molecules by focusing intensely on sequence and chemistry." In the near term, the drug giant is using RNAi as a research tool to speed up new-target discovery and validation—and increase the odds for its small-molecule and biologics pipeline. As former chief at Rosetta Inpharmatics, Sachs lived through the "Gee whiz, genomics!" bubble. "At Merck, we are way beyond the first blush of excitement about RNAi therapeutics and personalized medicine," he says. "We're way deep into actually figuring out how to get there over the next 50 years."

Silence Therapeutics A longtime biotech that moved into target validation, Silence jumped on RNAi with the acquisition of Berlin-based Atugen in 2005. Silence has an extensive and productive partnership with Quark Pharmaceuticals, a California RNAi drug and delivery shop equally new to the game; together they synthesized their own RNAi technology, dubbed AtuRx. This blunt-end siRNA lacks the classic two-nucleotide overhang, and is chemically modified for stability.

The Silence/Quark collaboration has made quick steps in the clinic. Pfizer is codeveloping their Phase IIa AMD agent, targeting the RTP801 gene via direct injection. Their drug for acute renal failure, aiming for the p53 gene via systemic delivery, is in Phase I. In addition, Silence snagged its first big deal last July when AstraZeneca offered $400 million in R&D milestones focused on respiratory diseases.

The biotech is also creating its own oncology pipeline, facilitated by a novel delivery system, AtuPlexa, which targets the endothelial cells lining blood vessels. "Our lead product, Atu027, goes after PKN3, a general cancer target involved in malignant cell growth and metastasis," says Silence CEO Jeffrey Vick, a biotech veteran. Preclinical tests showed that the blunt-end siRNA was active against a range of cancers. "But we saw exciting data against pancreatic and other GI cancers," Vick says. "The plan is to advance it into Phase I."

RXi Pharmaceuticals CytRx, a Los Angeles small-molecule discovery company, spun off its RNAi subsidiary as RXi in March. RXi's sits on some hot IP: long double-stranded RNAs, care of Craig Mello; hairpin siRNA, care of Cold Spring Harbor's Greg Hannon; and miRNA, care of its discoverer, Dartmouth's Victor Ambros.

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 RNAi process.

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.

A Macro Look at MicroRNA

Systemic delivery, target selection, chemical modification—all were riddles that RNA R&D has traditionally had trouble cracking. But over more than two decades, Crooke made a slew of discoveries that have helped grease the wheels of RNAi drug development. As a result, Alnylam and Isis, both leaders in their respective RNA niches, have long cross-licensed their IP. Last December, the two biotechs shook hands over a new miRNA development deal, the joint venture Regulus Therapeutics.

MicroRNAs are single-stranded RNA 21 to 23 nucleotides long that derive from short, siRNA-like, double-stranded RNAs. They function like to RNAi, binding to messenger RNA and regulating gene expression. But while RNAi targets a single gene and destroys it, miRNA has the power to regulate entire genetic networks and pathways without destroying target mRNAs. In general, the therapeutic aim is to turn off miRNA functions. Cancer cells, for example, make miRNAs that inhibit proteins that inhibit tumor growth. Block the miRNA, and the suppression is suppressed—and many normal pathways are turned back on. The opportunity to interfere in oncogenesis has Big Pharma hot on miRNA's trail.

Also located in Carlsbad, Regulus took only three months to snag a $100 million deal with GSK for rights to its four miRNAs for use in developing anti-inflammatory drugs. Regulus is also conducting R&D in oncology, inflammation and immunity, and cardiovascular diseases. CEO Kleanthis Xanthopoulos, who trained and taught at Sweden's Karolinska Medical Institute and later worked on the Human Genome Project, confesses a lifelong fascination with RNA. "It's the source of all life, compared to which DNA is just plain boring," he says.

Regulus may have a head start on miRNA IP, but Santaris Pharma A/S, a Danish biotech, can boast the first miRNA drug in clinical trials. In May, Santaris announced that its anti–hep C drug SPC3649, which targets mRNA-122, entered Phase I. An antisense survivor, Santaris has coined the term "RNA antagonists" to describe its pipeline of 11 antisense and miRNA agents. Its technology platform is based on locked nucleic acid (LNA) chemistry, which former CEO Keith McCullagh, who stepped down last month, claims is a major advance in both stability and target binding. GSK must be a believer, because in December it came calling with a $700 million R&D milestone deal to develop four miRNA-based therapies for viral infections. (The new CEO of Santaris is Soren Tulstrup, fresh from the VP spot at Merck Global Human Health.)

Rosetta Genomics is another force in miRNA R&D. The Israeli biotech has patented a large number of miRNA targets, and is poised to take a step toward personalized medicine when it markets the first microRNA diagnostic test this year, allowing doctors to identify hard-to-distinguish cancer types.

Patents Pending and Rending

In the absence of marketed drugs, most RNAi biotechs' value derives from their drug or delivery IP, and it's a fiercely competitive field. "We basically own the space," says Alnylam CEO John Maraganore. "We've obtained the critical elements of all fundamental patents—10 of the top 11 exclusively."

There are three key patents unlocking access to RNAi therapeutic R&D. Fire and Mello's description of long double-stranded interfering RNAs for gene silencing in worms—called the Carnegie patent—can be licensed by any researcher. Two other patents cover Thomas Tuschl's groundbreaking discovery of double-stranded–cum–overhangs siRNA in humans (Tuschl I) and his synthesis and use of this trigger to successfully silence genes (Tuschl II). Alnylam has exclusive rights to Tuschl II.

Yet Alnylam is no Scrooge. The biotech pursues an open-door policy when licensing its IP. "More research means better validation of its IP, and any advances translating IP and technology into actual drugs will benefit the entire field," says Barbara Bolten.

Tuschl II was issued in 2006, but the fate of Tuschl I, co-owned by MIT, UMass, the Whitehead Institute, and Max Planck, remains up in the air after seven years at the US Patent Office. Some critics claim that complications have arisen because it may have been amended to cover siRNA characteristics that could only have come to light through Tuschl's later experiments. Others suggest that its claims are simply too broad.

In fact, action has been taken on few of the more than 2,000 RNAi patent applications. Most experts agree that only when RNAi products approach the market will litigation and patent appeals force the pace to pick up.

Predictably, Alnylam's imperial IP claims are not universally admired. Most other shops publicly assert the uniqueness of their own RNAi compounds based on number of nucleotides, overhang, blunt or hairpin ends, chemical modifications, and the like.

Sirna's IP position causes sparks for a different reason: It is based largely on claims of exclusivity for identifying RNAi gene targets. To the chagrin of its competitors, the Patent Office issued Sirna the first ever target-specific RNAi patent—for a gene linked to asthma, arthritis, and cancer. In his blog, Dirk Haussecker dubs Sirna's a "brute-force approach," and quotes an anonymous insider, saying: "The siRNA community will address [target-specific] patents and unite to stop them. This will be a future battlefield."

This thicket of patent claims and disputes will inevitably grow even thornier. Although the clock is always running on market exclusivity, the RNAi patents are young, RNAi drug/target discovery is swift, and the first locally delivered products should reach market in a year or three. Of course, the downside of the platform's celebrated efficiency is that generic drugmakers will likely be able to copycat its cookie-cutter technology with nowhere near the difficulties posed by biosimilars.

Yet the efficiency should pay off in pricing. The top biotechs are moving experimental compounds through preclinical development in less than two years. As for manufacturing costs, one estimate offered the following comparison: If the average small-molecule drug costs $1, and the average biologic drug costs $100, an RNAi drug would weigh in at around $10. Coupled with the assumption that gene-based therapies offer a much higher rate of effectiveness, RNAi's value-for-cost equation may pleasantly surprise payers.

Off-Track With Off-Targets

Precious little is known about the long term effects of gene-silencing drugs based on siRNA or miRNA. Despite the model's target specificity and low-dose potency, there's growing concern about compounds aimed at such common targets as microRNA-122 to treat high cholesterol. While that gene has been validated as a regulator of LDL, there may be side effects to switching it off for months or years of treatment, especially since 70 percent of the liver's microRNAs are 122s.

The issue of off-target effects was at the center of a controversy last spring about Opko's Phase III bevasiranib for wet AMD. The drug appears to work well. Opko maintains that after its naked siRNA is injected into the eye, it enters the cells and carries out RNA interference, shutting down the VEGF gene responsible for blood vessel formation.

But after conducting his own test, Jayakrishna Ambati, an ophthalmologist and researcher at the University of Kentucky, told a different story. He asserted that bevasiranib never even got into the cells, and so never hit its target. Instead, the drug activated an immune system receptor, which in turn suppressed the AMD's wayward blood vessel growth. Ambati got the same results when he tested Allergan's siRNA-based AMD drug candidate targeting VEGF1R. He further found that random sequences of nucleotides—not just Opko's specific sequence—performed equally well. Published in Nature and reported in TheNew York Times last April, Ambati's study underwhelmed RNAi insiders, who have long known about this off-target interferon response.

Ambati's critique, however, went deeper. "[RNAi] seems to be working by a completely different mechanism unrelated to the underlying premise," Ambati told the Times. And he told Pharm Exec, "The term 'off-target' has lost all meaning in the field of RNAi. There is a specific target for these siRNAs independent of sequence. It is [the immune system]." Yet in his own experiments using accepted delivery systems such as encapsulating the siRNA in a lipid formulation, Ambati showed that once the naked siRNA is armored, it can get inside the cell and do its job.

Opko and Allergan officials both told the Times that their own studies showed that their products work as intended, through RNAi's mechanism of action. When contacted by Pharm Exec, Opko's Samuel Reich said, "I have nothing to say about the Ambati study," and hung up.

"The report suggested that the RNAi effect is not specific, although in fact it can be very easily shown in a lab that it specifically silences a target," says Barbara Bolten. "Opko will likely have to prove that its drug works the way it says it does to get FDA approval."

In March, when Alnylam CEO John Maraganore announced that Phase II results of its anti-RSV RNAi compound delivered the first-ever human proof of concept, City of Hope's John Rossi questioned whether the naked siRNA inhaled into the lung may be triggering the same immune response that is responsible for the antiviral effect. To Haussecker, the lesson of these dustups is clear: Do not rush RNAi drug candidates into the clinic; if the first RNAi drugs on the marker do not work as intended, the backlash could taint the entire class. "Alnylam fast-tracked its drug candidate to make good on its promise to Wall Street," he says, adding that both Alnylam and Sirna have postponed INDs for RNAi using systemic delivery to get better safety data.

Outcomes at FDA and Beyond

If biotechs are rushing to market, FDA is taking its usual go-slow approach. Isis and Genzyme got a rude awakening when agency officials reported that mipomersen, the Phase III antisense drug for high cholesterol, would require more safety data. Mipomersen's NDA for accelerated approval for its initial indication, a rare condition called homozygous familial hypercholesterolemia, will be postponed a year. But the planned filing for the much broader—and more lucrative—indication in high-risk, high cholesterol will be delayed until at least 2012 because FDA wants a cardiovascular outcomes trial, which typically eats up several years.

"Mipomersen works better than any drug I've ever dealt with," says Isis' Stanley Crooke. "But we're going through an extraordinarily negative pendulum swing at the FDA." Crooke and other RNAi execs view FDA's decision as less about RNA drugs than about the validity of high-cholesterol surrogate markers in the aftermath of the Vytorin debacle. Still, says Haussecker, odds are that the agency will require outcomes trials for any RNAi drug aimed at a previously untested target.

Will RNA interference and microRNA hasten a new era of personalized medicine and a wave of drugs for previously undruggable targets? Or will science's efforts to realize the medical benefits of this "gift from heaven" fall flat?

"Major pharma decision makers express optimism and confirm the market-disruptive nature of the [RNAi and] miRNA technology platform," Cantor Fitzgerald analyst Pamela Bassett wrote in a recent note.

But a more cautious Jim Niedel says: "I think there will be incremental solutions to systemic delivery that will lead to new drugs. But whether there will be a general solution and dozens of drugs may not be resolved for many years."

Perhaps Big Pharma's smartest move—other than signing billion-dollar development deals—could be to get out of the way. "I think the big advances will continue to come from biotechs," says Barbara Bolten. "They have deep expertise, are willing to take risks, and are completely focused."

As for RNAi insiders, they believe that they are starting a revolution. This year, Genentech will sign its own big deal with Alnylam, a move that will further erode doubts about RNAi, predicts Haussecker. "Even biologics are running out of good targets," he says. "For Big Pharma, RNAi is an obvious engine of innovation. When the leading biotechs start partnering with little RNAi companies, it shows how important the therapeutic potential of RNA interference is."