Alnylam–Isis Venture Regulus, Leader in MicroRNA Drugs, Aspires to Create New Paradigm of Treatments

10/24/08Follow @xconomy

Within the first five minutes of sitting down for an interview with Kleanthis Xanthopoulos, I could see this guy likes to think big. The idea behind his company, Regulus Therapeutics, is to show that a young technology called microRNA has the same sort of potential that gene-splicing techniques represented in the 1970s and targeted antibody drugs did in the 1980s. Xanthopoulos’ message is that this will take a long time, but when it pays off, it will pay off big.

“Companies like Biogen, Genentech, and Amgen were built on that powerful concept,” Xanthopoulos said when I visited his office in Carlsbad, CA a couple weeks ago. “Monoclonal antibodies went through a 15- to 20-year incubation period. It typically takes that long for a transformational technology to yield a tangible drug.”

Regulus is the progeny of a couple other companies built on big ideas. It’s a 50/50 joint venture between Cambridge, MA-based Alnylam Pharmaceuticals (NADSAQ: ALNY), an RNA-interference drug developer, and Carlsbad, CA-based Isis Pharmaceuticals (NADSAQ: ISIS), a pioneer in antisense drug technology. These companies pooled their intellectual property in September 2007 to test the still far-out concept of drugs that block microRNAs. These tiny strands of RNA weren’t discovered until 1993 in worms, and not until 2001 in humans. They are thought to hold huge potential as therapeutics, because they can affect not just one gene or protein in isolation, but full networks of genes—a strategy which might be useful in treating complex diseases like diabetes or autoimmunity, where multiple genes can get fouled up.

Xanthopoulos has some reason to be comfortable talking about a 20-year vision. Before Regulus was even six months old, it was approached by the world’s second-biggest pharmaceutical company, GlaxoSmithKline. In April, Regulus signed a collaboration with Glaxo worth $20 million upfront and as much as $600 million to develop microRNA drugs for inflammatory diseases.

Still, the work is at very early stages. The company hasn’t publicly identified a lead drug candidate. It’s going to be another 18 to 24 months before Regulus can expect to get its first drug tested in humans, Xanthopoulos says.

Regulus is pursuing this work with a staff of 22. Xanthopoulos, an Xconomist, was previously a managing director at Enterprise Partners in San Diego, and was a co-founder and CEO of Anadys Pharmaceuticals (NASDAQ: ANDS). Earlier in his career, in the mid-1990s, he was a section head within the National Institutes of Health, where he worked on the Human Genome Project.

During his days at the NIH, Xanthopoulos and his colleagues looked at long stretches of the 6-billion letter sequence of the human genome and saw vast areas that were “non-coding”—they didn’t appear to provide instructions for making any molecules that performed any sort of bodily function. Those stretches were branded “junk DNA” for years, wrongly. “It was right under our noses. We thought it was uninteresting, but it was,” Xanthopoulos says.

A simple PubMed search shows three scientific papers in the NIH’s database on microRNA in 2001, and an exponential curve rising from there to 1,000 papers in 2007, Xanthopoulos says. By late 2006, early 2007, Isis CEO Stanley Crooke and Alnylam CEO John Maraganore realized that each of their companies had critical technologies that could be used for microRNA drug development. “It was too big of an opportunity to address by small groups within the companies,” Xanthopoulos says. “There was tremendous interest from VCs. Big ideas don’t come along that often. Once every five or 10 years, maybe. To have a huge idea, and have the technologies here that you can plug and play is unheard of. That’s what exciting about Regulus.”

I asked Xanthopoulos help me understand the biology of what he’s talking about.. MicroRNAs, he explained, have evolved over hundreds of millions of years to regulate the on-off switches of genes. They play complex roles, not well understood by biologists, that let them, for instance, fine-tune the immune system’s T cells to attack foreign invaders like viruses while sparing the body’s own healthy cells, Xanthopoulos says. It’s a complicated, delicate balance that can be profoundly disturbed if just a few mircoRNAs go awry. “Think of an orchestra, a symphony, where 100 musicians are playing in harmony, and the conductor knows who’s playing what instrument, and at what frequency,” Xanthopoulos says. “If three or four musicians are off key, it will kill the music.”

So Regulus’ idea is to develop antisense drugs that will bind with and block these microRNAs, keeping them from disrupting the symphony and allowing the body to get back into homeostasis, or a balanced state. Conventional small-molecule drugs and antibodies aren’t able to hit these microRNA targets, he says.

There’s plenty of unknown here, and plenty of risk, given that none of these microRNA blockers has ever been tested in humans. Even so, venture capitalists have been pushing hard to get a piece of the action, and at least five companies are pursuing this opportunity, Xanthopoulos says, including Bothell, WA-based MDRNA and Seattle-based Mirina. He expects more to join the fray, but says that his company has key intellectual property in the field. “All of them are going to have to come to Regulus at some point to get freedom to operate,” Xanthopoulos says. “But the field is going to continue to move forward.”

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