The experimental drug has startling powers: It can turn down a mutant gene in a patient’s body, stopping the production of proteins that cause a terribly painful rare disease.

A crucial, late-stage clinical trial showed that the drug works—and that it’s safe. And now the biotech company behind it, Alnylam, is poised to bring this first-of-its-kind therapy to market.

The news has thrilled both patients and scientists, who have been working for decades on the technology to mute misbehaving genes, known as RNA interference, or RNAi. They’ve understood for two decades how the biology works. But it’s been a long, slow slog to figure out how to deliver RNAi therapies to the right cells safely and effectively. Alnylam alone has spent 15 years, and more than $1 billion, on the effort.

So does the company’s recent success herald an explosion of new drugs that can shut down troublesome genes?


The RNAi delivery systems remain highly complex—and the most effective technologies are still protected by patents that make it difficult for startups to get into the field. Safety concerns persist with other RNAi drugs in development: Last year, for instance, Alnylam had to scrap revusiran, one of its most advanced drugs. Rather than alleviating it, the drug exacerbated pain in a rare nerve disease called transthyretin amyloidosis. And several patients died in the clinical trial, though it’s still not clear exactly why. Alnylam’s stock plummeted by half on that news.

The issue of safety has haunted the RNAi field for many years now: Although it’s possible to silence the impact of genes, early work has resulted in several off-target effects that create unforeseen toxicities. So the major focus of RNAi research in recent years has been drug delivery: how to safely deposit the RNAi load to the right tissues, minimizing the impact on other bodily functions. And that’s proven challenging. While it’s working, for now, in diseases of the liver, the field still needs to validate whether RNAi can work in other organs.

Alnylam is testing seven RNAi drugs in the clinic, for conditions ranging from hepatitis B to high cholesterol. A handful of other companies are also in the field, working on therapies that treat diseases of the central nervous system or enhance cancer immunotherapy. But we’re unlikely to see a flood of startups suddenly raising tens of millions to pursue RNAi.

“I don’t think you’ll see new companies popping up in RNA interference. The intellectual property around the field is too constraining,” said Doug Fambrough, CEO of RNAi competitor Dicerna Pharmaceuticals.

Still, the field does have enormous promise —and market potential.

Most drugs work by targeting ill-formed or malfunctioning proteins and trying to excise them from the body. RNAi, by contrast, goes after the genetic source of the faulty protein production and shuts that system down.

When it works, it can ease symptoms in patients with no other options.

Alnylam’s lead RNAi drug patisiran, aimed at treating a rare nerve disorder called familial amyloid polyneuropathy, is projected to ultimately exceed $1 billion in worldwide sales at its peak, which is expected in 2023. The drug, which is being developed in conjunction with Sanofi, should be up for review by the Food and Drug Administration in a couple months, and will be up for European regulatory approval next year.

Alnylam’s stock shot up so much on the news, its market capitalization now exceeds $11 billion.

“Alnylam’s results came out with a bang, not a whimper,” said Alnylam CEO John Maraganore. “It highlights the fact that these medicines can really be transformative, turning off production of genetic disease.”

A big win in worms proves tough to translate to humans

The phenomenon of RNA interference was first observed in the 1990s in nematodes, and in 1998 scientists Andrew Fire and Craig Mello published a seminal paper in Nature that demonstrated these roundworm genes could be silenced. The duo won the Nobel Prize in 2006 for their work. By that point, several companies had already launched to try to develop new RNAi-based therapeutics—including Alnylam.

Expectations were high — and so was the pressure to create a groundbreaking medicine.

Then came the roadblocks. Scientists hit hurdle after hurdle. And many companies began to crumble: While gene silencing was simple in worms, mammals proved to be far more complex—and safe drug delivery emerged as a major problem. When RNAi therapies weren’t delivered to the right tissues, dangerous side effects showed up in humans that weren’t predicted through animal models. The drugs just weren’t working.

The most dogged RNAi companies—Alnylam among them—began to study better methods to deliver these therapeutics to the right tissues. And a few different techniques have since emerged to improve drug delivery, and, by extension, safety—such as Alnylam’s approach of binding the RNAi therapeutic to a lipid nanoparticle, or fat, to help it settle in the liver. Another method used broadly by RNAi companies is “GalNAc”—a sugar derivative that’s attached to RNAi drugs to help it safely work in the liver.

Both have shown preclinical promise, and the lipid nanoparticle approach was used with patisiran to great effect in Alnylam’s positive trial. So the initial hurdles of safe RNAi delivery finally seem surmountable.

“Nobody will put [RNAi therapies] back in the box, therapeutically,” said Phil Sharp, a scientific co-founder of Alnylam and winner of his own RNA-related Nobel Prize. “They are now alive and out there, and more and more people will see them as answers to their problems.”

Still, Sharp cautioned: “It took 15 years to get here, and the next 10 years will be exponentially more impactful. But we won’t see this matured as a pharmaceutical approach for decades.”

A handful of biotechs chase a revolution

The closest approximation to another RNAi success comes from Ionis Pharmaceuticals and Biogen, which last year received approval for Spinraza, a drug aimed at spinal muscular atrophy. Children with the disease don’t produce enough of a protein called SMN, and the drug works by amplifying the gene that produces the protein—allowing the body to create more of it. It is, in a sense, the opposite of gene silencing, but it’s another proof point that validates the general concept of creating drugs that mute or amplify defective genes.

It’s also proof of concept that a successful RNAi therapy can be quite lucrative.

Spinraza is priced at $750,000 for the first year of treatment and $375,000 for each subsequent year. (Alnylam has not yet indicated how it will price patisiran if it wins FDA approval.)

Meanwhile, other biotechs working on RNAi continue to churn along. Arbutus Therapeutics just landed a $116 million investment from Roivant Sciences to speed development of its RNAi tech as well as other therapeutic platforms in development.

RXi Pharmaceuticals is pursuing RNAi therapeutics in a broad array of diseases, from warts to cancer. Arrowhead Pharmaceuticals and Wave Life Sciences have a number of preclinical programs in play, though none have advanced nearly as far as Alnylam.

Dicerna Pharmaceuticals, meanwhile, is preparing to enter the clinic with an RNAi drug that treats primary hyperoxaluria—a rare genetic disease that causes the overproduction and buildup of substances called oxalates in the urine. The company’s therapeutic aims to turn off the enzyme that creates all the excess oxalate.

Alynlam’s success boosted the stock of many of these biotechs; Dicerna’s share price jumped 21 percent immediately after Alynlam released its data on Sept. 20 and has increased steadily ever since.

A surge of interest in back-to-basics research

The bull case for RNAi draws from biotech history. As many in the industry point out, monoclonal antibodies have become a hugely lucrative and important therapeutic class—but their development was just as fraught, with just as many hurdles, as RNAi. Scientists finally solved the biggest problems, and by 2024, the market is expected to top $130 billion globally.

RNAi could hit great heights, too, if it can be made to work outside the liver.

“If we can expand the role of RNAi to other organ systems beyond the liver, the likelihood that RNAi could overtake antibodies in terms of importance for diseases of man, animals, and even plants, is certainly there,” said Dr. Geert Cauwenbergh, president and CEO of RXi Pharmaceuticals. “It’ll just take work, like anything else.”

Gene Yeo, an RNA researcher at University of California, San Diego, thinks he can break that liver barrier. He’s building on the ideas of RNAi to form his own startup, Locana Therapeutics. The company aims to use CRISPR gene-editing to craft RNA therapeutics that can be delivered into the central nervous system—clearly a daunting task for most drug makers.

By editing the RNA, the company hopes to find therapies for neurodegenerative diseases like Huntington’s and ALS.

“I think the lessons we extract from Alnylam’s successes have a little more to do with the idea of delivery,” Yeo said. “The field was mired by the delivery problem—that is, getting the compounds to the right tissues, and right cell types—and get a durable response. But now we see that we can do that.”

Madhu Lal-Nag, a researcher at the National Institutes of Health who coordinates RNAi research, said she’s starting to see a surge of interest in the field among academics who want to unravel more of the basic science, especially as it becomes clear that other hot fields of research, such as CRISPR gene-editing, face their own series of hurdles.

“Everyone jumped on the CRISPR-Cas9 bandwagon, but there are a host of things that we don’t know about genome-editing that we’re now beginning to see,” Lal-Nag said. “I think that’s been responsible for people going back and taking a look at RNAi. Better the devil you know.”

Republished with permission from STAT. This article originally appeared on October 5, 2016