Intellia Therapeutics on Monday revealed new evidence that an infusion of a CRISPR gene editing medicine into the body could treat a rare inherited illness, bolstering earlier study results that were viewed as a landmark moment for the Nobel Prize-winning technology.
Treatment with the medicine, developed by Intellia and Regeneron Pharmaceuticals, significantly reduced levels of a misshapen protein that causes the disease transthyretin amyloidosis, with effects lasting as long as a year so far. The highest dose tested appears to be more potent than lower ones, a sign drugmakers look for when testing a new therapy. Side effects were mostly mild.
"The data continue to look great," said Kiran Musunuru, a professor of medicine at the University of Pennsylvania who specializes in CRISPR gene editing, in an interview. The signs of durable benefit are "encouraging" and suggest the effects might "end up being lifelong," he added. Musunuru wasn't associated with the study and reviewed the results for BioPharma Dive on the condition he not share them.
Intellia had made a press release summarizing the results available to BioPharma Dive prior to disclosing them publicly. The company declined, however, to provide presentation slides with more detailed findings, which will be presented on a conference call Monday afternoon.
The results appear to add to an early, but growing, body of data that CRISPR gene editing performed inside the body may be used to treat disease. Intellia and another biotech company, Editas Medicine, are the first to bring such medicines into clinical trials. (A CRISPR Therapeutics treatment for sickle cell disease, also in human testing, edits genes outside the body.)
"What we've hoped for is what we're seeing," said Intellia CEO John Leonard in an interview. For gene editing in the body, there's now "a lot more reason to think that the story will only get bigger with time."
Intellia's findings, while encouraging, leave important questions unanswered. It's unclear whether the company's treatment will have an equivalent or greater impact on the disease than available medicines, or whether the benefits will diminish with time, as has been observed in tests of different types of genetic medicines. Long-term safety risks, if they materialize, may not arise for years. Some experts have also wondered if there are unintended consequences to permanently reducing levels of the target protein, called transthyretin or TTR.
Nonetheless, Intellia's progress increases the likelihood that gene editing could become a treatment option for transthyretin amyloidosis, or ATTR, a potentially deadly disease that's been targeted by a number of drugmakers.
ATTR can be either inherited or acquired and is characterized by the toxic buildup in the body of misfolded TTR, which normally carries vitamin A. The disease can cause progressive nerve or heart damage, leading to a wide range of health problems.
For many years, ATTR patients had few effective treatments. But, recently, their options have improved significantly. Alnylam Pharmaceuticals and Ionis Pharmaceuticals each brought drugs to market that silence the gene responsible for producing TTR, stopping or even reversing disease progression for people with nerve damage. A pill from Pfizer that stabilizes the protein can reduce the risk of death for ATTR patients with heart damage known as cardiomyopathy.
Each drug has limitations, though. Alnylam's and Ionis' medicines, sold respectively as Onpattro and Tegsedi, require frequent infusions or injections and must be taken for life. Pfizer's pill Vyndamax is also taken regularly, and covering the high cost of treatment can be difficult, patient advocates have said.
Intellia's treatment, which uses gene editing tools in an attempt to permanently halt production of the protein, could be a one-and-done alternative. So far, however, the company only has results in patients with nerve damage, which are typically classified separately from those with heart damage.
Last June, results published in The New England Journal of Medicine showed the protein levels of six patients who received the lowest two doses Intellia has tested fell by an average of 52% and 87%, respectively, four weeks after treatment. The data were described by outside experts as an important proof point for CRISPR gene editing drugs.
Monday's results are from nine additional patients who received one of two higher doses of Intellia's treatment. The lower dose led to an average 86% protein reduction in three patients, comparable to what Intellia disclosed last June. For the six patients who received the highest dose, TTR levels fell an average of 93%.
Those numbers surpass the 80% reduction reported in testing of Onpattro, a bar Intellia needs to clear. The company is betting that higher TTR suppression will lead to better health outcomes for ATTR patients, though that hasn't been proven. "Every little bit matters," Leonard said. "We're aiming for as much as we can get."
Intellia didn't disclose how each study volunteer's TTR levels changed over time, but showed averages over the first two months for each dose group in its presentation. In an interview, executives noted that treatment effects held up for as long as one year for some patients on the lowest dose and as long as six months for those on the highest dose.
For the high-dose group, the 93% average TTR reduction was "exactly the same" after six months as after one month, according to Ian Karp, senior vice president of corporate communications at Intellia. "On average," the company hasn't seen any waning effects, he said.
The results were most consistent at the highest dose, whereas they were less predictable on the lowest dose, Leonard added. Data showed a slight decline in average percentage protein reduction for that group during the follow-up period.
Side effects were mainly classified as mild, and were most commonly headache, back pain and rash. There were no abnormalities on lab tests for elevated liver enzymes, an important finding given the stress the treatment could put on the liver.
One serious adverse event judged related to treatment, vomiting, did occur in a single patient who received the highest dose. That patient had a history of gastroparesis that previously led to stays in the hospital. "He got fluids and was fine thereafter," Leonard said. Nonetheless, the incident led Intellia to test the highest dose in more patients — six instead of three — to further evaluate its safety.
The case "doesn't seem either a showstopper or particularly related to the drug," Musunuru said, adding that the findings justify the excitement surrounding Intellia's initial results last year.
That excitement caused the market values of associated developers of CRISPR gene editing drugs to climb by nearly $10 billion combined, Luca Issi, an analyst at RBC Capital Markets, recently estimated. Intellia's shares peaked at over $170 apiece last summer.
The share prices of all of them, including Intellia, have crashed back down amid a broader market downturn for biotech. But Issi and other analysts have speculated that Intellia's updated results may "reinvigorate" the gene editing field.
Intellia will now press forward with what Leonard says is an increasing focus on ATTR cardiomyopathy. Onpattro and Tegsedi aren't yet approved for those patients, whose disease is faster-moving, deadlier and more common. "It's a space we want to move into very, very quickly," Leonard said. "We see the window as wide open at this point."
Intellia hopes to finish enrolling cardiomyopathy patients in its Phase 1 trial this year. A pivotal study targeting those patients is planned as well. The company is seeking regulatory permission to use a fixed dose, rather than the weight-based doses it's been testing, because it would be easier to roll out commercially, according to Leonard.
But while the need for a new ATTR cardiomyopathy treatment is greater, so are the study hurdles. A pill being developed by BridgeBio Pharma for cardiomyopathy patients, for example, failed a Phase 3 trial in December.
BridgeBio pinned the outcome on placebo recipients faring unusually well and still believes it can succeed by continuing the trial. But the surprising result shook investor confidence in other cardiomyopathy studies, including an Alnylam trial that should produce data this year.
Leonard says Intellia is keeping an eye on all of them. Their results will show whether BridgeBio's study is an outlier, he added, which could influence Intellia's plans.
"We have the advantage of going later," Leonard said. But "we are absolutely paying deep attention."
Editor's note: This story was updated with additional details on the data contained in Intellia's presentation.