An infusion of an experimental CRISPR gene editing medicine has shown early promise as a treatment for a rare inherited condition, an encouraging finding that marks the latest, significant step forward for a technology awarded a Nobel prize last year.
Treatment with the medicine, which was developed by Intellia Therapeutics and Regeneron Pharmaceuticals, dramatically lowered levels of a misshapen protein that causes the disease transthyretin amyloidosis. Side effects in the six patients enrolled in Intellia's study were few and mild.
The results, which were published Saturday in The New England Journal of Medicine, are the first clinical evidence that CRISPR gene editing can be used successfully inside a person's body to treat disease.
"This is a landmark event in modern medicine," said Kiran Musunuru, a professor of medicine at the University of Pennsylvania who specializes in CRISPR gene editing and wasn't associated with the study. "I think it's going to open the door to a whole new class of therapies."
While encouraging and powerful proof of concept, the initial data from Intellia's study don't yet answer many of the most pressing questions facing CRISPR. It's unclear how long the effects researchers observed will last, or whether they'll vary as more patients are treated. The long-term safety consequences of gene editing are also unknown.
Additionally, multiple drugs are available in the U.S. to treat transthyretin amyloidosis, potentially complicating Intellia's path forward with regulators, doctors and patients.
"We have effective tools that suppress [the protein] at this point," said John Berk, a physician who treats amyloidosis at Boston Medical Center and associate professor of medicine at Boston University School of Medicine. "And we have the luxury of regulating them."
Transthyretin amyloidosis, or ATTR for short, can either be inherited or acquired. The less common hereditary form is estimated to affect some 50,000 people worldwide. Its telltale sign is the buildup of misfolded clumps of TTR, a protein the body normally uses to ferry vitamin A.
ATTR impacts each patient differently but is consistently progressive, worsening over time. Some have nerve damage that begins with toe numbness and creeps upwards, causing health problems like a loss of bowel control or compromised mobility. For others, the disease corrodes the heart, leading to heart failure and death within a few years. Many have elements of both.
For many years, the only treatments were liver transplants or a generic drug called diflunisal that could stabilize the transthyretin protein and slow nerve damage.
Since 2018, however, three new medicines have won approval in the U.S. Alnylam Pharmaceuticals, a pioneer of a gene silencing method known as RNA interference, secured Food and Drug Administration clearance of an infused medicine called Onpattro that can improve nerve function. Akcea Therapeutics followed with Tegsedi and Pfizer's Vyndamax, which is similar to diflunisal, was OK'd for ATTR patients with heart problems.
"When these drugs were approved it was like, 'Oh finally, at least there's something we can do,'" said Mary O'Donnell, the president of the nonprofit Amyloidosis Foundation.
But the drugs have limitations. O'Donnell says patients often have trouble accessing or covering the costs of Vyndamax. Onpattro requires a multi-hour infusion every three weeks so its effects won't wane, along with steroids to prep patients for each treatment. Tegsedi can have a negative impact on kidney function and blood-clotting platelets. All three must be taken for life.
Those drugmakers, and others, are working on longer-lasting and more convenient options. But none offer the potential of gene editing, which is meant to permanently halt, or even reverse, the disease's downward course.
"When we think about what gene editing can bring, it's not just convenience," said Intellia CEO John Leonard. "This is about improving prospects."
The first look
The clinical success of Onpattro and Tegsedi proved suppression of the TTR gene could change the trajectory of the disease.
In some ways, Intellia is building on what Alnylam has already done. Alnylam spent years figuring out how to safely and effectively deliver RNA drugs into cells. The biotech finally succeeded by focusing on the liver, a large organ that filters blood, and using tiny fat bubbles known as lipid nanoparticles to get them there.
"I think what Intellia has done is sort of take the playbook from Alnylam," said Berk, of BU. Berk has been an investigator in the trials of multiple approved ATTR drugs and advised Intellia in the past.
Like Alnylam, Intellia uses lipid nanoparticles to shuttle its medicine into the liver. Inside each, however, are the genetic instructions for CRISPR editing tools. Once absorbed into liver cells, those instructions are deployed to precisely cut the segment of DNA that encodes for TTR, thereby breaking it and halting production of the harmful protein at its genetic source.
Intellia is co-developing its treatment with Regeneron, which partnered with the smaller biotech in a wide-ranging alliance signed in 2016.
As with other drugs just beginning testing in humans, Intellia's trial was primarily designed to find the optimal dose to move into further testing — one that strikes the right balance between safety and efficacy. Intellia is enrolling adults between 18 to 80 years old with inherited ATTR and symptoms of nerve damage. Some, not all, have heart damage. They'll be tracked for two years.
The results published in NEJM, which are also being presented at a medical conference on Saturday, are from three patients who received a low dose and three given a higher one.
After four weeks, results from the first three on the lower dose showed TTR protein levels fell by an average of 52%. For the three given a higher dose, the reduction was much greater — on average 87%, with a range of 80% to 96%.
Those latter numbers surpass the 80% reduction reported in testing of Onpattro, an important bar for efficacy.
"It's not just that it worked, it's that it worked so well," said Musunuru, of UPenn. For TTR levels to fall by up to 96%, he added, essentially all of the liver's cells must be edited.
"That's essentially saturation editing," he said. "That's a home run."
Reported side effects, which included headaches, nausea and an infusion-related reaction, were minor. Abnormalities on lab tests for blood clots or elevated liver enzymes — a key concern given the stress the treatment could put on the liver — were "barely detectable," Intellia's Leonard said.
Saturday's results are the first glimpse at how well Intellia's treatment might work. They do not yet prove CRISPR gene editing can benefit patients any more than existing drugs. While Onpattro and Tegsedi require chronic dosing, they've already been shown to keep transthyretin levels down for multiple years, with their effects leading to better health outcomes for patients with polyneuropathy. It's unclear whether greater TTR suppression would offer an improvement.
"Kudos to Intellia for crafting a CRISPR/cas9 that worked," said BU's Berk. "The novelty is employing new biology to suppress TTR — but the concept of TTR suppression in this disease is well established."
Berk is wary of permanently driving down transthyretin levels, as Intellia's medicine is designed to do, even though that hasn't yet been shown to negatively affect people other than requiring vitamin A supplements.
The potential for accidental, off-target edits to DNA also exists, which could have real health risks such as damage to a gene that helps suppress cancer. Laboratory testing of extremely high doses of Intellia's medicine in human liver cells found no evidence of off-target editing and researchers expect the DNA changes introduced by treatment to be "of low risk." But that may not be known definitively for years. Study participants will have long-term monitoring for safety.
"It's exciting to see that there's evidence of efficacy," said Matthew Wheeler, a Stanford University cardiologist who specializes in genetics and works at Stanford's Amyloid Center. "But there are a lot of safety-related questions that are unanswered."
Wheeler also remains concerned about the potential of gene editing-induced changes being passed on to children, although Intellia's treatment isn't designed to affect sperm or egg cells.
The FDA appears to have taken a stricter stance on genetic medicines for diseases that already have effective treatments. The agency, for instance, is requiring lengthier follow-up for multiple gene therapies in development for the blood disease hemophilia. It's not known what the regulator will require of a gene editing treatment for ATTR. So far, the FDA has asked developers to prove benefits beyond TTR reduction.
"We will draw from some of the work that's been done by others," said Leonard.
Intellia intends to test an even higher dose as well as prove its treatment can similarly lower TTR levels in people with heart damage. A dose will then be selected for pivotal testing in both types of patients, so the drug "can be approved for patients with whatever form of amyloidosis," Leonard said.
Intellia's results are the latest milestone in a string of research landmarks set since 2012, when a paper from Jennifer Doudna and Emmanuelle Charpentier laid out the biochemical components of how CRISPR gene editing worked.
Scientists in academic labs and biotech companies like Intellia have harnessed the tool, which is both more powerful and easier to use than previous methods, across medicine and agriculture. The outpouring of research has made many careers as well as led to immense controversy, such as when Chinese researcher He Jiankui shocked the world with his announcement of the birth of two girls from embryos edited by CRISPR.
Other CRISPR-focused biotechs have made history before Intellia, which was founded by Doudna and others. CRISPR Therapeutics entered clinical testing with a CRISPR gene editing medicine first. Study results over the past year and half have proven its treatment can dramatically alter, and potentially cure, the blood diseases beta thalassemia and sickle cell.
But the biotech creates its treatment by editing patient cells outside the body. Those cells are modified using CRISPR and then reinfused. The complex process has safety risks of its own and limits the reach of gene editing to diseases that can be treated through altered stem cells.
That's why Intellia's results represent a step forward for CRISPR. The inside-the-body approach involves its own set of challenges, most notably delivering the medicine to the right place and ensuring the right cells are edited. But proving it can be done opens a new chapter in gene editing research.
Intellia has several experimental treatments meant to edit genes with a single infusion. So does Editas Medicine, which could report initial results later this year for an in vivo CRISPR treatment it's developing for a rare form of genetic blindness. Verve Therapeutics, which Musunuru co-founded and went public this month, also has an inside-the-body gene editing treatment for heart disease that could enter clinical testing next year.
"Until now we really didn't have any evidence that if you put CRISPR or any gene editing tool directly in the human body, it would be both effective as well as — as far as we can see from this study — safe," he said. "This is the first clinical trial that convincingly shows that yes, [in vivo] gene editing can work and can work very well."