NEW YORK – Intellia Therapeutics is betting what was once the first in vivo CRISPR gene-editing treatment to enter late-stage clinical development in the US could, within the next few years, hit the market.
Intellia, which traces its roots back more than a decade to when it was founded by CRISPR pioneer Jennifer Doudna and others in 2014, has ambitions of having one of the first commercial in vivo CRISPR gene-editing candidates and transitioning to a commercial-stage company. In January, on the heels of trimming its pipeline and workforce, Cambridge, Massachusetts-based Intellia announced plans to commercialize its first three products by 2030.
One of those products, nexiguran ziclumeran (nex-z), is currently being investigated in a Phase III trial, dubbed the MAGNITUDE trial, which started treating patients last year. It's the furthest along of the drugs Intellia has advanced into Phase III testing, where the company is evaluating it as a treatment for transthyretin (ATTR) amyloidosis, a rare, severe, and progressive disease caused by abnormal TTR proteins that misfold and accumulate, specifically in patients who also have cardiomyopathy (ATTR-CM).
Intellia was able to advance directly from its Phase I trial of nex-z in ATTR-CM to a Phase III trial based on evidence from other studies that suggested lowering TTR is likely to benefit patients. For example, in the open-label Phase I trial of nex-z, which is ongoing, all 36 patients who received nex-z exhibited a reduction in TTR protein levels after one year, with the cohort experiencing, on average, about a 90 percent reduction in TTR levels, said David Lebwohl, chief medical officer at Intellia, citing data published in the New England Journal of Medicine in November. Most patients also had no change or even improved in terms of their heart failure disease severity based on a classification developed by the New York Heart Association.
Those outcomes have been consistent over time, Lebwohl said. In 11 patients treated during the Phase I trial who had at least two years of follow-up data, TTR reductions have been sustained. "From patient to patient, basically every patient gets very close to that 90 percent," he said, adding that "it looks like it's going to be a permanent change."
There are two main types of ATTR amyloidosis, and Intellia believes nex-z could be an effective treatment for both. ATTR-CM is the more common type, primarily affecting the heart, though it's still considered a rare disease. ATTR-CM can be hereditary or associated with aging, in which case patients have the wild-type TTR gene that produces proteins that are initially normal, but later in life these proteins become unstable, misfold, and accumulate. Meanwhile, in ATTR amyloidosis with polyneuropathy (ATTR-PN), which primarily affects the nervous system, the disease is always hereditary and caused by TTR genetic mutations.
Nex-z, previously known as NTLA-2001, is designed to inactivate the TTR gene to reduce TTR protein levels overall, regardless of genotype. Nex-z was developed as part of a multitarget discovery, development, and commercialization collaboration with Regeneron, under which Regeneron has rights to discover and develop CRISPR-based drugs for in vivo liver targets, among other disease settings, which could be advanced by either company or codeveloped. For nex-z, Intellia leads development and commercialization.
The idea behind nex-z, which is designed as a one-time treatment, is that by preventing production of TTR proteins, the treatment should be able to halt or even beat back the disease.
There are existing treatments on the market for ATTR-CM. Patients might, for example, take drugs to ease certain symptoms, such as diuretics to address heart failure, and there are multiple disease-modifying therapies.
However, while these drugs slowed disease progression in clinical trials, compared to placebo, they aren't improving symptoms, Lebwohl noted. "People are still getting worse over time," he said. "There are still signs of progression of the disease."
For example, there are daily oral medications, including Pfizer's Vyndamax (tafamidis) and BridgeBio Pharma's Attruby (acoramidis), that try to stabilize TTR proteins to stop them from misfolding. Other drugs focus on ATTR-PN and are only indicated for patients with the hereditary form of disease, such as RNA silencing drugs from Alnylam Pharmaceuticals like Onpattro (patisiran), a small interfering RNA drug that's designed to prevent production of TTR, and Amvuttra (vutrisiran), an RNA interference drug that's also separately being studied as a treatment for hereditary and wild-type patients with ATTR-CM. These RNA silencers are administered through an intravenous infusion every few weeks, for Onpattro, or subcutaneously quarterly, for Amvuttra.
Nex-z could offer an interesting approach as a one-time treatment, which may be appealing for patients who don't live near a medical center and for whom repeated visits aren't convenient, or who worry about treatment burden, said Ahmad Masri, principal investigator for the MAGNITUDE trial at the Oregon Health & Science University and an associate professor in the cardiovascular medicine division at the university's medical school.
"It's an exciting technique," he said.
Historically, ATTR-CM has been underreported, in part because only patients with the most severe symptoms would receive the necessary heart biopsy to diagnose it, Masri said. With improved imaging techniques over the past decade, the disease can now be diagnosed noninvasively, such as with echocardiograms and electrocardiograms.
After patients are diagnosed with ATTR-CM, they undergo genetic testing to determine whether they have a mutated or wild-type TTR gene. That's even the case for older patients, Masri noted, even though they're likely to have the age-related form of ATTR-CM with a wild-type TTR gene. Knowing a patient's genotype can inform whether to consider cascade testing for family members and help determine the appropriate course of treatment, since some treatments for ATTR-PN are only indicated for those with a TTR mutation.
"It's vital to do this," Masri said of genetic testing. At OHSU, "we are currently doing it in every single patient."
In his experience, about 90 percent of patients with ATTR-CM have wild-type TTR, while only 10 percent have a TTR mutation, Masri said, though it can vary for different populations. Patients with West African ancestry, for example, are more likely to have a TTR mutation than patients from other ancestry groups.
For the global, randomized-controlled Phase III MAGNITUDE trial of nex-z, Intellia aims to enroll 765 patients with heart failure — but clinically stable symptoms — and a diagnosis of ATTR amyloidosis with cardiomyopathy and either mutated or wild-type TTR. Intellia expects to complete the clinical trial by early 2027, potentially filing a biologics license application (BLA) with the US Food and Drug Administration by 2030.
As an in vivo gene editor, nex-z doesn't require apheresis or myeloablative conditioning like the only CRISPR-based drug currently on the market, an ex vivo gene-editing product developed by Vertex Pharmaceuticals and CRISPR Therapeutics for sickle cell disease and transfusion-dependent beta thalassemia, as well as other ex vivo candidates in clinical development.
For nex-z, administration involves a single outpatient infusion.
"Unlike a lot of gene-directed therapies, it's actually very simple to get these drugs," Lebwohl said. The day before nex-z administration, the patient receives a dose of steroids to try to avoid infusion-related reactions, and the day of treatment they receive steroids and antihistamines, followed by a four-to-six-hour intravenous infusion of nex-z itself.
Researchers in the MAGNITUDE trial will evaluate the treatment's efficacy based on a composite endpoint comprising cardiovascular-related mortality and events, as well as track metrics like hospitalizations and changes from baseline in TTR protein levels.
Intellia is also testing nex-z in patients with ATTR-PN and expects to begin treating patients in the Phase III MAGNITUDE-2 trial this year. Its other therapeutic development focus is NTLA-2002 in hereditary angioedema (HAE), a rare genetic disease characterized by unpredictable and painful swelling attacks. Intellia last month treated the first HAE patient in the Phase III HAELO trial.
If Intellia sees positive results from the MAGNITUDE trial, it will file an application with the FDA in the hopes of being able to bring nex-z to market for ATTR-CM. And, depending on nex-z's success in clinical testing, Lebwohl said Intellia plans to explore whether the gene-editing therapy could help early-stage patients with ATTR amyloidosis and prevent the onset of symptoms.
"That's ultimately what will be very exciting," Lebwohl said.