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.

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.