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."

Improving prospects

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."

An Intellia Therapeutics scientist in the lab

Courtesy of Intellia Therapeutics


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."

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