Most HAE patients attack-free after NTLA-2002 treatment in trial
50 mg dose led to 80% reduction in attacks vs. placebo over 4 months
Most people with hereditary angioedema (HAE) who received treatment with a 50 mg dose of the gene-editing therapy NTLA-2002 in a Phase 2 clinical trial were free from swelling attacks over nearly four months, according to a new study.
Compared with a placebo, the 50 mg dose led to an 80% reduction in swelling attacks over weeks 1-16 of the trial. While the results were slightly less striking with a lower 25 mg dose, 40% of these patients also experienced no attacks during the 16-week follow-up period, compared with none of those given the placebo.
Findings from the trial were detailed in “CRISPR-Based Therapy for Hereditary Angioedema,” a study published in The New England Journal of Medicine. The work was funded by Intellia Therapeutics, the company developing NTLA-2002.
Bolstered by these findings, Intellia has selected the 50 mg dose for further testing in its ongoing Phase 3 clinical trial. That trial, called HAELO (NCT06634420), is still recruiting an estimated 60 adults with HAE types 1 and 2 at a site in California, with more study centers expected to open soon.
“These positive NTLA-2002 Phase 2 results underscore the tremendous potential of our … gene editing therapy to be a functional cure and redefine the treatment paradigm for HAE,” John Leonard, MD, president and CEO of Intellia, said in a company press release. “What was previously an unimaginable potential to be free of chronic therapy is one step closer to becoming a reality for the HAE community.”
Gene-editing therapy NTLA-2002 tested in Phase 2 clinical trial
Hereditary angioedema, or HAE for short, is a genetic disorder marked by the overproduction of bradykinin, a signaling molecule that normally prompts blood vessels to widen, and increases blood vessel permeability to control blood pressure. When produced in excess, bradykinin can cause fluid to leak into surrounding tissues, triggering the swelling attacks that are the hallmark feature of HAE.
Bradykinin is produced by an enzyme called kallikrein. NTLA-2002 is a one-time therapy that uses the gene-editing technology CRISPR to inactivate a gene that provides instructions to make a precursor of kallikrein. This is expected to permanently reduce levels of this enzyme, thereby lowering bradykinin production and ultimately preventing swelling attacks.
“Approved HAE therapies can reduce but frequently do not eliminate all angioedema attacks and require chronic administration, resulting in a significant treatment burden and a major impact on the quality of life for people living with HAE,” said Danny Cohn, MD, PhD, lead principal investigator of the Phase 2 study at Amsterdam University Medical Center.
The new data come from a Phase 1/2 clinical trial (NCT05120830) testing NTLA-2002 in adults with HAE. Findings from the Phase 1 part of the study, which evaluated three different doses of the gene editing therapy — 25, 50, and 75 mg, given as a single infusion into the vein — showed that most patients given NTLA-2002 were free from attacks after up to 1.5 years.
The Phase 2 part of the study included 27 people with HAE types 1 or 2. Among them, 10 received a one-time infusion of NTLA-2002 at a dose of 25 mg and 11 received an infusion at a higher dose of 50 mg, while the remaining six patients received a placebo infusion. The participants were followed for at least 16 weeks, or about four months.
The results showed that the gene-editing therapy significantly reduced rates of swelling attacks among participants. Over the 16-week follow-up, four of the 10 patients given low-dose NTLA-2002 were completely free from attacks.
In the high-dose group, meanwhile, eight of 11 patients were free from attacks over the initial 16 weeks. Importantly, according to the researchers, all eight have remained completely free from attacks as of the latest assessment without needing additional treatments.
By contrast, none of the patients given a placebo were free from attacks over the initial 16 weeks. Statistically, rates of attacks with either dose of NTLA-2002 were more than 70% lower than with a placebo over this period. Those reductions were similar for attacks needing on-demand treatment and moderate to severe attacks.
After 16 weeks, long-term prophylaxis, or preventive treatment, was resumed for most of the HAE patients in the placebo group (67%), compared with one patient in each NTLA-2002 dose group.
According to Leonard, “the Phase 2 data demonstrated that a majority of patients in the 50 mg arm experienced a complete response — no attacks at all and no further treatment needed — after a one-time infusion of NTLA-2002 through the latest follow-up.”
This was “consistent” with long-term data from the trial’s Phase 1 portion, Leonard said.
“We are highly encouraged by these results, which we believe sets NTLA-2002 apart from other prophylaxis treatments,” Leonard added.
No serious side effects seen with HAE treatment in trial
NTLA-2002 overall was well tolerated in the study, with no serious side effects reported. The most common safety issues noted were headache, fatigue, and the common cold.
Cohn said he is “optimistic that NTLA-2002 will change the way we treat HAE and put an end to the need for a lifetime of chronic treatment,” adding, “These NTLA-2002 Phase 2 data are remarkable, showing this investigational therapy could permanently stop swelling attacks with a single infusion.”
Consistent with findings from the Phase 1 portion, biomarker data also indicated that the gene-editing therapy decreased levels of the kallikrein enzyme as designed. Reductions were, on average, 55% for those given the low dose and 86% for patients who received the 50 mg dose.
These NTLA-2002 Phase 2 data are remarkable, showing this investigational therapy could permanently stop swelling attacks with a single infusion.
Hilary Longhurst, PhD, a study investigator at the University of Auckland, said in a separate press release that “this reduction is perhaps the most crucial as it shows us that the therapy is working” as intended.
“Kallikrein acts as messenger that triggers swelling and in patients with HAE, this protein is basically let loose. The fact that we can reduce its presence tells us that we’re on the right track,” Longhurst said.
Overall, the researchers concluded that their findings “support continued investigation [of NTLA-2002] in a larger phase 3 trial.”
“These results show the potential of a single dose of … NTLA-2002 to be a functional cure for patients with hereditary angioedema,” the team wrote.
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