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.

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."