Single dose of NTLA-2002 seen to reduce monthly HAE attacks 95%

Pivotal Phase 3 trial of gene-editing therapy expected to launch this year

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by Steve Bryson, PhD |

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Intellia Therapeutics’ experimental gene-editing therapy NTLA-2002 reduced the number of monthly swelling attacks by 95% among 10 people with hereditary angioedema (HAE) treated in the Phase 1 portion of a Phase 1/2 clinical trial, according to newly published data.

The single-dose treatment also led to sustained, dose-dependent reductions in blood levels of kallikrein, an enzyme that’s overactive in HAE. While mild infusion-related reactions were reported, most of them resolved on the day of treatment, the researchers noted.

“We witnessed a dramatic decrease in the number and severity of attacks in patients after a single dose of NTLA-2002, a major point of progress for treating this severe disease,” David Lebwohl, MD, Intellia’s executive vice president and chief medical officer, said in an emailed statement to Angiodema News. “We are excited for what NTLA-2002 could mean for people with HAE, their caregivers and physicians.”

A pivotal Phase 3 trial testing the therapy’s efficacy in larger numbers of patients is expected to launch in the second half of this year, pending feedback from regulatory agencies. Its data, if positive, will support a future application seeking NTLA-2002’s approval.

The trial findings from the Phase 1 portion were reported in a new study, titled “CRISPR-Cas9 In Vivo Gene Editing of KLKB1 for Hereditary Angioedema” and published in The New England Journal of Medicine.

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Swelling attacks in the deep layers of the skin — the hallmark symptom of HAE — are caused by the overproduction of bradykinin, a molecule that regulates blood pressure and inflammation. Bradykinin production, in turn, is controlled by an enzyme called kallikrein.

Standard treatment includes preventive and/or on-demand therapies that often require lifelong dosing to help manage swelling attacks. Nevertheless, breakthrough HAE attacks still may occur.

“Despite currently available treatments, people living with hereditary angioedema continue to face frequent anxiety about their next swelling attack,” John Leonard, MD, president and CEO of Intellia said in a company press release.

“The interim NTLA-2002 clinical data published suggest that a single dose of NTLA-2002 may eliminate angioedema attacks,” Leonard said.

NTLA-2002, which uses the CRISPR/Cas-9 gene-editing system, is designed to lower the body’s levels of bradykinin by disrupting the activity of the KLKB1 gene. This gene encodes a kallikrein precursor called prekallikrein. As such, NTLA-2002 is expected to prevent swelling attacks with a single treatment, rather than the lifelong therapy now often needed.

Dosing recently began in the Phase 2 portion of the Intellia-sponsored Phase 1/2 study (NCT05120830). Spanning up to two years, this phase is testing two doses of NTLA-2002 against a placebo in HAE patients. Data from this portion of the study is expected later this year, according to Leonard.

The study’s Phase 1 portion, whose data now were reported, evaluated the effects of three doses of NTLA-2002 — 25, 50, or 75 mg — in 10 HAE patients, ages 26-73. NTLA-2002 was administered intravenously, or directly into the bloodstream, via a single infusion over a minimum period of two hours.

After a 16-week, or about four-month, primary observation period following dosing, the participants were monitored for a total of 104 weeks, or about two years.

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All but 1 patient had no HAE attacks for about 1 year after treatment

In the 90 days before the study, the participants experienced from three to 54 HAE swelling attacks.

Interim data showed there were no reported swelling attacks in nine of the 10 participants for up to about one year after treatment.

Blood tests revealed that NTLA-2002 reduced kallikrein protein levels in a dose-dependent manner. Kallikrein dropped by 67% in the group given 25 mg, by 85% in the group receiving a 50 mg dose, and by 95% in those given 75 mg. These responses were sustained for up to 48 weeks, or almost one year.

During the primary observation period, the mean number of attacks per month fell by 91% in the 25 mg group, by 97% in the 50 mg group, and by 80% in the 75 mg group. Across all 10 participants, there were 95% fewer attacks per month and 93% fewer that required on-demand treatment.

“In this small study, a single dose of NTLA-2002 led to robust, dose-dependent, and durable reductions in total plasma kallikrein levels, and no severe adverse events were observed,” the researchers wrote, noting also that “reductions in the number of angioedema attacks per month were observed at all dose levels.”

In the six participants who experienced up to 14 attacks per month and were on prophylaxis by the time they entered the study, previous long-term preventive treatments were withdrawn between 2.6 and 5.4 months after NTLA-2002 dosing. No additional attacks have been reported in these patients.

These data provide additional support that our in vivo CRISPR-based genome editing approach may eliminate angioedema attacks for patients.

No dose-limiting toxic effects were observed.

The most common adverse events were infusion-related reactions (70%) and fatigue (60%). Mild (grade 1) infusion-related reactions resolved on the day of treatment, while one moderate (grade 2) infusion reaction resulted in back pain, which temporarily interrupted treatment. No serious events were noted.

Elevated levels of liver enzymes suggestive of liver damage were seen in 60% of the patients. These elevations were mild and all resolved within eight weeks. While all patients developed antibodies against the Cas9 protein, as expected, there was no observable impact on treatment.

“These data provide additional support that our in vivo CRISPR-based genome editing approach may eliminate angioedema attacks for patients,” Leonard said in the emailed statement to Angiodema News.

“We see these findings as truly remarkable and reinforce our belief that NTLA-2002 could address the significant treatment burden that exists for people living with HAE. We look forward to advancing NTLA-2002 and expect to begin a Phase 3 study later this year, pending regulatory feedback,” Leonard added.