Navenibart shows potential as long-acting preventive therapy for HAE
Antibody safely sustained kallikrein inhibition in healthy adults in trial
The use of the antibody navenibart, being developed by Astria Therapeutics to prevent swelling episodes in hereditary angioedema (HAE), resulted in the sustained inhibition of kallikrein — an enzyme that’s overactive in HAE patients — in healthy volunteers in a clinical trial, supporting its potential as a long-acting therapy, data show.
For doses of 300 mg or more given via an under-the-skin (subcutaneous) or into-the-vein (intravenous) injection as part of the Phase 1a trial (NCT05477160), it took an average of 82-105.5 days for navenibart levels in the body to drop by half. These results suggest that the therapy may only need to be given to patients once or twice every six months, according to the researchers.
The data, previously presented in part at a scientific meeting, have now been published in a study titled “Safety and pharmacokinetics of long-acting plasma kallikrein inhibitor navenibart (STAR-0215) in healthy adults” in the Annals of Allergy, Asthma & Immunology.
“We are thrilled by … the opportunity to provide additional information that affirms our belief in navenibart’s potential to become the first-choice therapy for HAE,” Christopher Morabito, MD, Astria’s chief medical officer, said in a company press release.
Astria is now recruiting for a Phase 3 clinical trial that’s testing the medication in adults with PAH.
Phase 3 trial testing navenibart now enrolling adults with HAE
Based on the early data from the Phase 1a trial, the company advanced navenibart into ALPHA-STAR, a Phase 1b/2 study (NCT05695248) in people with HAE type 1 or type 2, ages 18 and older. HAE type 1 is the most common form of the disease, seen in more than 80% of patients, with type 2 accounting for most other cases.
ALPHA-STAR evaluated the safety and efficacy of navenibart in 29 HAE patients across 20 study sites in North America and Europe. The results showed the treatment was safe and reduced the frequency of monthly swelling attacks by up to 95% when given every three or six months.
The Phase 3 program, designed to introduce a potentially life-changing HAE therapy to eligible participants around the globe, is underway.
A five-year open-label extension called ALPHA-SOLAR (NCT06007677) and ALPHA-ORBIT (NCT06842823), a placebo-controlled Phase 3 trial, are now underway. The ALPHA-ORBIT trial, which is expected to provide the data needed to file for regulatory approval, is enrolling up to 145 individuals with a diagnosis of HAE type 1 or type 2. Top-line data are expected in early 2027, according to the company.
“The Phase 1a trial in healthy subjects laid the foundation for the advancement of navenibart and charted a path toward initiating ALPHA-ORBIT, our currently enrolling pivotal Phase 3 trial. The Phase 3 program, designed to introduce a potentially life-changing HAE therapy to eligible participants around the globe, is underway,” Morabito said.
Angioedema occurs when fluid builds up in tissues, resulting in episodes of swelling that can arise in different parts of the body. In HAE, this is due to genetic mutations that lead to the excessive production and release of bradykinin. Too much bradykinin causes blood vessels to become more permeable and leak fluid into tissues.
Navenibart, previously known as STAR-0215, is designed to block the activity of kallikrein, an enzyme that mediates the release of bradykinin and is overactive in HAE. This is expected to reduce bradykinin levels, which should help prevent swelling.
Blood levels of long-acting therapy candidate seen for over 7 months
The Phase 1a trial involved 41 healthy adults, with a mean age of 38.8, who were randomly assigned to receive either increasing doses of navenibart — 100 to 1,200 mg subcutaneously or 600 mg intravenously — or a placebo. Slightly more than half of the participants were men, and were Black or African American individuals.
After a single dose of navenibart, the therapy’s levels in the blood increased quickly and stayed measurable for at least 224 days, or longer than seven months, except in the 100 mg group. For doses of 300 mg or more, levels stayed above the target threshold for at least 84 days, or nearly three months.
According to the researchers, these data support the potential of navenibart as a long-acting therapy with spaced dosing. This is relevant because “currently approved long-term prophylactic therapies for HAE attacks incur substantial treatment burden through frequent dosing,” the team noted.
Navenibart significantly blocked the activity of kallikrein in the blood, with effects seen as early as four days after a single dose. Doses of 300, 600, and 1,200 mg led to up to 35%, 55%, and 65% inhibition, respectively, lasting up to 224 days for the highest dose.
Higher doses of navenibart resulted in higher levels in the blood, the data showed. The average half-life of navenibart — the time it takes for its levels to drop by half — was 82 days for the 300 mg, 92 days for the 600 mg, 94 days for the 1,200 mg subcutaneous doses, and 105 days for the 600 mg intravenous dose.
The therapy also was well tolerated, per the data. The rate of side effects was similar between navenibart and the placebo, and there were no serious side effects. The most common side effects reported with navenibart were reactions at the site of injection and headache. Most reactions were mild, and all injection site reactions resolved within two days.
“In conclusion, navenibart was well tolerated in a first-in-human study and demonstrated effective inhibition of plasma kallikrein, with an extended half-life,” the researchers wrote. These data “support the continued clinical development of navenibart in individuals with HAE.”
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