Rare diseases affect about 25 to 30 million Americans. There are more than 6,800 rare disorders, and the vast majority of them don’t have treatments. But positive results from phase 3 clinical trials using a technique called RNA interference (RNAi) have the biotech and rare disease worlds abuzz.
Last week, Alnylam, a Cambridge, Massachusetts-based startup, announced that its RNAi drug patisiran, halted the progress of a life-threatening genetic disorder called hereditary ATTR amyloidosis with polyneuropathy in more than half of patients. If all goes well, the RNAi drug could be approved by the Food and Drug Administration sometime next year.
It’s a big deal, not just for those with hereditary ATTR amyloidosis but for other orphan diseases as well, because it could open up the field to a completely new class of drugs that attack disease at the source: the gene.
Until now, even if researchers knew which gene caused a particular disease that was not nearly enough to create a treatment or a cure. That’s because biology is devilishly complex: DNA must turn into RNA that in turn holds instructions for constructing a particular protein. Then the protein must be produced. Once they’re fabricated, proteins then interact inside cells to do particular things, sometimes for good, and sometimes for ill.
So many steps are involved in understanding the typical disease process that the economics don’t work in favor of developing treatments for diseases that only affect a couple hundred thousand people. That’s how diseases get orphaned.
Most drugs that make it to market today work by interfering with proteins that cause problems, typically by blocking or replacing a particular protein.
Alnylam’s drug, patisiran, works in a different way: It disrupts the RNA messaging so that the problematic protein never gets produced in the first place. This way, the RNAi agent can “silence” the gene.
If the gene remains unchecked in hereditary ATTR amyloidosis, an abnormal number of proteins get deposited in various parts of the body. Gradually, these deposits rob patients of their motor ability. They become unable to walk, dress themselves, or even use utensils. Most die within 15 years of diagnosis.
But in a phase 3 study of 225 patients from 19 countries, more than 90 percent of those who received patisiran infusions experienced a halt in disease progression. More than half of patisiran patients also showed significant improvements in sensory, motor, and autonomic neuropathy symptoms after 18 months.
Alnylam’s announcement of these positive results come nearly 20 years after the RNAi mechanism first was described in 1998 by Craig Mello and Andrew Fire, then professors at the University of Massachusetts and the Carnegie Institution. Alnylam was founded in 2002. And Mello and Fire received the Nobel Prize in Medicine in 2006 for their RNAi work.
But turning RNAi insights into actual drugs has been a rocky road. In the early 2000s, many pharmaceutical companies — including Roche, Pfizer, Abbott, and Merck — invested hundreds of millions in RNAi projects. The thinking was if a disease had a well-defined genetic target but no treatment, maybe RNAi could be the solution.
Early clinical trials failed to live up to the hype. Some RNAi agents provoked dangerous immune reactions. Others could not be proven effective. Even more challenging, if RNAi was injected into the bloodstream, it tended to break down before it could reach its target. By 2010, most companies had shuttered their RNAi labs.
Alnylam soldiered on. It researched the RNAi process in many different mammals, strengthening the case that the mechanism could be useful in humans. It pioneered new ways of delivering RNAi agents to diseased cells, using lipid nanoparticles as well as a specialized sugar molecule (Ga1NAc). Their studies showed that most of these RNAi vectors ended up in the liver, so many of the dozen or so drugs in the Alnylam pipeline are designed to target a variety of liver ailments.
After 15 years of trying, Alnylam seems to be on the cusp of getting an RNAi drug approved. Other startups are also exploring whether RNAi agents could be useful in fighting viral infections or cancer. As companies refine the technology, RNAi therapies could finally come to the clinic.