Intellia Releases First Clinical Data, CRISPR Gene Editing Reaches a 'Milestone' Moment

An infusion treatment for an experimental CRISPR gene-editing drug has shown early promise in treating a rare genetic disease. This encouraging finding marks the latest and significant step forward for the technology that won the Nobel Prize last year.

The drug, developed jointly by Intellia Therapeutics and Regeneron Pharmaceuticals, significantly reduced levels of the abnormal protein that causes transthyretin amyloidosis (ATTR). Among the six patients in the Intellia study, reported side effects were few and mild.

The results, published in the New England Journal of Medicine on Saturday, are the first clinical evidence of CRISPR gene editing successfully treating a disease inside the human body.

"This is a milestone event in modern medicine," said Kiran Musunuru, a professor of medicine at the University of Pennsylvania and a CRISPR gene-editing expert who was not involved in the study. "I think it will open the door to a whole new class of therapies."

Although these preliminary data are encouraging and provide strong proof of concept, they still fail to answer many pressing questions facing CRISPR technology. It remains unclear how long the effects observed by researchers will last, or whether they will vary as more patients are treated. The long-term safety consequences of gene editing also remain unknown.

Additionally, several drugs are already available in the United States to treat ATTR, which could complicate Intellia's path forward with regulators, physicians, and patients.

"We already have effective tools to suppress this protein," said John Berk, a physician at Boston Medical Center who treats amyloidosis and an associate professor of medicine at Boston University School of Medicine. "And we have the means to regulate them."

Improved prospects

Transthyretin amyloidosis (ATTR) can be hereditary or acquired. The rarer inherited form is estimated to affect about 50,000 people worldwide. It is characterized by the accumulation of misfolded clumps of the TTR protein—a protein the body normally uses to transport vitamin A.

ATTR affects each patient differently, but it is progressive and worsens over time. Some patients develop nerve damage that begins with numbness in the toes and spreads upward, leading to health problems such as bowel incontinence or impaired mobility. Others suffer heart damage, leading to heart failure and death within a few years. Many patients have both symptoms.

For years, the only treatments were liver transplantation or a generic drug called diflunisal, which stabilizes transthyretin and slows nerve damage.

However, since 2018, three new drugs have been approved in the United States. Alnylam Pharmaceuticals, a pioneer in the gene-silencing approach RNA interference, received U.S. Food and Drug Administration (FDA) approval for its infusion drug Onpattro to improve nerve function. Akcea Therapeutics' Tegsedi followed, and Pfizer's Vyndamax (similar to diflunisal) was also approved for ATTR patients with heart problems.

"When these drugs were approved, it felt like 'Oh, finally, at least we can do something,'" said Mary O'Donnell, president of the nonprofit Amyloidosis Foundation.

But these drugs have limitations. O'Donnell said patients often struggle to access or afford Vyndamax. Onpattro requires infusions lasting several hours every three weeks to prevent the effect from waning, along with steroids to prepare for each treatment. Tegsedi can negatively affect kidney function and blood-clotting platelets. All three drugs require lifelong use.

These pharmaceutical companies and others are developing longer-acting, more convenient options. But none holds the promise of gene editing to permanently halt or even reverse the disease's progression.

"When we think about what gene editing can bring, it's not just convenience," said John Leonard, CEO of Intellia. "It's about improving prospects."

First observations

The clinical success of Onpattro and Tegsedi proved that suppressing the TTR gene can alter the course of the disease.

In some ways, Intellia is building on what Alnylam has already achieved. Alnylam spent years studying how to safely and effectively deliver RNA drugs into cells. The biotech company ultimately succeeded by focusing on the liver—a large organ that filters blood—and using lipid nanoparticles (tiny fat bubbles) to deliver the drug to the target location.

"I think Intellia has borrowed Alnylam's strategy," said Berk of Boston University. Berk has served as an investigator in trials of several approved ATTR drugs and has consulted for Intellia.

Similar to Alnylam, Intellia uses lipid nanoparticles to deliver the drug to the liver. However, inside each particle are the genetic instructions for the CRISPR editing tool. Once absorbed by liver cells, these instructions are deployed to precisely cut the DNA segment encoding TTR, thereby disrupting the gene and fundamentally preventing the production of the harmful protein.

Intellia is developing the therapy with Regeneron, which partnered with the smaller biotech company in a broad alliance agreement signed in 2016.

Like other drugs just beginning human testing, Intellia's trial is primarily designed to determine the best dose for further testing—one that strikes the right balance between safety and efficacy. Intellia is recruiting adults aged 18 to 80 with hereditary ATTR and symptoms of nerve damage. Some, but not all, also have heart damage. They will be followed for two years.

The results published in the New England Journal of Medicine (also presented at a medical conference on Saturday) come from three patients who received a low dose and three who received a higher dose.

After four weeks, results from the first three patients on the low dose showed TTR protein levels fell by an average of 52%. For the three patients on the higher dose, the reduction was greater—an average of 87%, ranging from 80% to 96%.

These numbers exceed the 80% reduction reported in the Onpattro trial, an important efficacy benchmark.

"Not only does it work, it works very well," said Musunuru of the University of Pennsylvania. He added that TTR reductions of up to 96% imply that nearly all liver cells were edited. "This is essentially saturation editing," he said. "It's a home run."

Reported side effects included headache, nausea, and infusion-related reactions, all mild. Laboratory abnormalities regarding blood clots or elevated liver enzymes—a key concern given the stress the treatment could place on the liver—were described by Intellia's Leonard as "barely detectable."

Saturday's results are the first demonstration of the potential effect of Intellia's therapy. They do not yet prove that CRISPR gene editing benefits patients more than existing drugs. While Onpattro and Tegsedi require long-term administration, they have been shown to maintain transthyretin levels for years, with effects that improve health outcomes in patients with polyneuropathy. It remains unclear whether stronger TTR suppression will lead to further improvements.

"Credit to Intellia for developing an effective CRISPR/Cas9," said Berk of Boston University. "The novelty is using new biology to suppress TTR—but the concept of suppressing TTR to treat the disease is well established."

Berk is cautious about permanently lowering transthyretin levels, although no negative effects on people have been shown so far other than the need for vitamin A supplementation. Gene editing could cause off-target DNA changes, which might pose real health risks, such as damaging genes that help suppress cancer. Laboratory tests of very high doses of Intellia's drug in human liver cells found no evidence of off-target editing, and researchers expect the DNA changes introduced by the treatment to be of "low risk." But this may take years to clarify. Study participants will undergo long-term safety monitoring.

"Seeing evidence of efficacy is exciting," said Matthew Wheeler, a cardiologist and genetics expert at Stanford University who works at the Stanford Amyloidosis Center. "But there are still many safety-related questions that remain unanswered."

Wheeler is also concerned that changes caused by gene editing could be passed on to children, although Intellia's therapy is not designed to affect sperm or egg cells.

The FDA appears to have taken a stricter stance on gene drugs for diseases where effective treatments already exist. For example, the agency has required longer follow-up for several gene therapies for hemophilia under development. It is unclear what requirements regulators will impose on gene-editing treatments for ATTR. So far, the FDA has asked developers to demonstrate additional benefits beyond lowering TTR.

"We will draw on some of the work other companies have already done," Leonard said.

Intellia plans to test higher doses and demonstrate that its treatment similarly lowers TTR levels in patients with heart damage. It will then select a dose for confirmatory trials in both types of patients, so the drug "can be approved for patients with any form of amyloidosis," Leonard said.

Extending CRISPR

Intellia's results are the latest in a series of research milestones since 2012, when Jennifer Doudna and Emmanuelle Charpentier published a paper describing the biochemical composition of CRISPR gene editing.

Scientists in academic labs and biotech companies like Intellia have harnessed this tool in medicine and agriculture, as it is more powerful and easier to use than previous methods. A flood of research has built careers and sparked great controversy, such as when Chinese researcher He Jiankui shocked the world by announcing the birth of two girls edited with CRISPR in embryos.

Other CRISPR-focused biotech companies made history before Intellia, which was founded by Doudna and others. CRISPR Therapeutics was the first to bring a CRISPR gene-editing drug into clinical testing. Results over the past year and a half have shown that its treatment can significantly alter or even potentially cure blood diseases such as beta thalassemia and sickle cell disease.

But that biotech company manufactures the treatment by editing patients' cells outside the body. These cells are modified with CRISPR and then infused back. This complex process carries its own safety risks and limits gene editing to diseases that can be treated with modified stem cells.

That is why Intellia's results represent a step forward for CRISPR. The in vivo approach involves its own set of challenges, most notably delivering the drug to the right location and ensuring the correct cells are edited. But proving its feasibility opens a new chapter in gene-editing research.

Intellia has several experimental therapies designed to edit genes with a single infusion. So does Editas Medicine, which may report preliminary results later this year from its in vivo CRISPR therapy for a rare inherited form of blindness. Verve Therapeutics, co-founded by Musunuru and listed this month, also has an in vivo gene-editing therapy for heart disease that could enter clinical testing next year.

"So far, we really haven't had any evidence that if you put CRISPR or any gene-editing tool directly into the human body, it can be both effective and—as far as this study goes—safe," he said. "This is the first clinical trial to convincingly show that in vivo gene editing can work and work very well."