measured in months, not years. (One could say about any recent development, “Oh, that’s so October,” joked Editas chief technology officer Vic Myer.)
Already used in labs across the world to alter the genes of practically every organism, CRISPR-Cas9 is, as many people have said, the democratization of gene editing, because it is much easier to use than zinc fingers and TALENs. One sign of its progress is that the first programs to reach the clinic could be what were once considered the far horizon. They are close enough, in fact, that they are among the programs Intellia and Editas have chosen to keep wholly owned.
Both have bigger partners that want to use CRISPR-Cas9 to make edits in cells that are extracted from a patient’s body, modified ex-vivo, then reinserted into the patient with hopes of curing a blood-borne disease. (Intellia’s partner is Novartis, and Editas has teamed up with Seattle’s Juno Therapeutics.) But the biotechs have reserved for themselves in vivo applications–the trick of sending the CRISPR-Cas9 scissors into the body to find the right cells and make the right cuts.
It’s a more complicated proposition than ex vivo modification. When CRISPR-Cas9 burst onto the biomedical scene three years ago, many observers figured the ex vivo applications would reach the clinic first.
That still might come true. Crispr Therapeutics CEO Rodger Novak predicted recently that some academic centers with biotech-like resources might start ex vivo clinical trials by the end of 2017. But at least one gauntlet has been thrown on the side of in vivo therapies. Editas said last year its in vivo program to correct a rare form of blindness could start clinical trials in 2017.
Intellia is going full-bore after diseases that start in the liver. Getting drugs to the liver without causing mischief or getting intercepted by the immune system is trickier than an injection into the eye, but Intellia has its reasons. The liver is the Rome of the body. All roads—or all blood vessels—eventually lead to the liver, so anything injected into the bloodstream, if constructed carefully enough, should get there. There are also myriad liver diseases. Intellia has prioritized four: Transthyretin amyloidosis (ATTR), a joint effort with Regeneron; alpha-1 antitrypsin deficiency; hepatitis B infection; and inborn errors of metabolism.
The fourth on that list isn’t one disease, it’s a grouping of rare diseases caused by a single gene gone awry. But going after inborn errors raises some of the most critical questions for Intellia, or for any company looking to deliver personalized medicine in a society where the regulatory and financial structures might not be ready to handle it.
Many of the inborn error diseases have only tens of patients, not hundreds or thousands. Viewed on a bar chart of liver diseases—the higher the bar, the more patients per disease—these diseases look like a long, low tail stretching far to the right. “I want to find a way to sweep up the tail,” says Intellia chief medical officer John Leonard. “If we have a solution for a disease with 100 people, why shouldn’t we do it?”
But here’s the problem. There might be so few patients, that a clinical trial would essentially have to involve most of them, leaving few, if any, to treat with a commercial product. And no company ever made money just by doing clinical trials. But as Sarepta Therapeutics (NASDAQ: [[ticker:SRPT]]) just found out, skimping on the trial size—it believed it could get a Duchenne muscular dystrophy drug approved with data from 10 patients—met with skepticism this week from FDA scientists and advisors. (Sarepta believed the FDA would be open-minded; a final vote on the drug is due in late May.)
As Leonard puts it, “How do we do trials if the trial is the treatment?” Leonard speculates that Intellia would have to work with regulators essentially to re-use data from one disease to another. For example, if a trial demonstrated that a company’s core gene-editing machinery was safe in one disease, would the FDA accept it as safe in another? Instead of starting each program from scratch, Leonard would like to find a process “that what I learn on one thing is applicable somehow to the next thing. I have no idea how the FDA feels about this.”
The very reason CRISPR-Cas9 is easy to use could eventually be a factor. Its molecular “scissors”—the cutting enzyme Cas9—stay the same in therapies for different diseases. What changes in a therapy, depending on the gene being targeted, are the guides: the strands of manufactured RNA that match up with the target and show Cas9 where to snip. It’s theoretically one less new component to test for each new drug program. Could that lessen the clinical expense, or lower the number of people needed for a trial?
It’s hard to say, but philosophical shifts in the way certain drugs are regulated will likely be necessary.
Leonard is optimistic that a different question, just as crucial, has already met with a favorable outlook at FDA: How do you prove to the agency that what was
