HAE attacks drop with infrequent navenibart dosing in early trial
Therapy given every 3 or 6 months also improved quality of life
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The experimental therapy navenibart was well tolerated and was associated with fewer swelling attacks and improved quality of life in adults with hereditary angioedema (HAE) when given every few months in an early clinical trial, a study showed.
“The proof-of-concept data … suggest that infrequent administration of navenibart every 3 months … or every 6 months … may be effective as a potential preventative treatment for individuals with HAE,” the researchers wrote.
Early trial tested navenibart in adults with HAE
Final data from the Phase 1b/2 ALPHA-STAR clinical trial (NCT05695248) were described in the study, “Open-label phase 1b/2 trial of navenibart, a long-acting plasma kallikrein inhibitor for hereditary angioedema,” published in the Journal of Allergy and Clinical Immunology. The trial was sponsored by Astria Therapeutics, a wholly owned subsidiary of Biocryst Pharmaceuticals and the developer of navenibart. Several co-authors are Astria employees.
The ongoing Phase 3 ALPHA-ORBIT trial (NCT06842823) is testing the medication against a placebo in a larger number of patients. The study is currently recruiting people ages 12 and older with HAE types 1 and 2, the most common forms of the disease, at sites worldwide.
HAE is a chronic genetic condition that causes sudden attacks of swelling in the tissues of the skin and mucous membranes. These attacks, a characteristic symptom of HAE, can substantially affect day-to-day life.
Excessive activity of a regulatory enzyme called kallikrein contributes to swelling in HAE. Kallikrein increases the production and release of bradykinin, a signaling molecule that causes blood vessels to widen. With too much kallikrein, bradykinin signaling can become overactive, and blood vessels may leak fluid into the surrounding tissue, causing swelling.
While several approved treatments for HAE work by targeting the kallikrein-bradykinin pathway to help prevent swelling attacks, current long-term preventive therapies may require dosing from daily to monthly, and some injection-based options are associated with injection-site pain.
Navenibart designed for less frequent dosing
Astria designed navenibart, an antibody-based therapy that blocks kallikrein, to overcome these challenges. Delivered via subcutaneous (under-the-skin) injection, it has an extended half-life, meaning it remains longer in the blood and may allow dosing every three or six months. In this trial, no injection-site pain was reported, which researchers suggested may be related to navenibart’s citrate-free formulation.
Navenibart received orphan drug designation in the U.S. and European Union for treating HAE. This status is intended to help speed the therapy’s clinical development and regulatory review.
In ALPHA-STAR, investigators tested the medication in 29 adults with HAE types 1 or 2. Their mean age was 46.4 years, and they began experiencing symptoms at a mean age of 13.3.
One group of patients received a single 450 mg dose. A second group received 600 mg followed by 300 mg three months later, and a third group received two 600 mg doses about one month apart. After data from the first 16 participants were reviewed and showed positive effects, enrollment was expanded, adding 13 patients to the two multidose groups.
Final data showed that navenibart was associated with an 86.3% reduction in the average monthly swelling attack rate, from 2.23 attacks before treatment to 0.31 attacks during the treatment period.
HAE attack rates remained low through 6 months
The monthly attack rate remained low through six months in all groups. A blood biomarker of plasma kallikrein activity also remained reduced for at least six months after treatment began.
Substantial reductions in attack rates were seen across the treatment groups and for more severe attacks, including events that required emergency treatment.
“Navenibart lowered the rate of HAE attacks of all severities, as well as the rate of attacks treated with on-demand medication over a prolonged period, consistent with results reported from injectable HAE preventative therapies,” the researchers wrote.
Almost half of participants (48%) were attack-free during the full treatment period. Others continued to have attacks, generally at reduced rates, while three participants experienced more attacks during treatment.
The researchers hypothesized that this might be related to individual variability in HAE symptoms and responses to the medication. “Complete elimination of attacks may not be obtainable in all patients, even with potent [preventive treatment],” they wrote.
Throughout the trial, participants in all groups reported clinically meaningful improvements in quality of life.
Navenibart was generally safe and well tolerated. No severe or serious treatment-emergent adverse events, deaths, or treatment discontinuations due to side effects were reported. The most common adverse events were headache, the common cold, and urinary tract infections. Three participants experienced injection-site reactions involving redness, itchiness, rash, or swelling, but none reported pain.
Long-term testing continues in extension study
All 29 ALPHA-STAR participants enrolled in a long-term, open-label Phase 2 extension study called ALPHA-SOLAR (NCT06007677). Early results from the extension study have suggested that navenibart injections every three or six months continue to reduce HAE attack frequency.
In the ongoing ALPHA-ORBIT, participants will be randomly assigned to receive either one of three navenibart dosing regimens or a placebo. The primary goal is to measure changes in HAE attacks over six months of treatment.
ALPHA-ORBIT results could support an application for regulatory approval of navenibart for HAE. “If approved, navenibart would be the first extended half-life … antibody treatment offering infrequent dosing while maintaining [blood] kallikrein [blockage] for long-term prevention of HAE attacks,” the team wrote.
