PHILADELPHIA — The investigational drug navenibart reduced attacks of hereditary angioedema by an average 91% over 1 year with only twice-yearly dosing and no serious adverse effects or safety signals, according to a phase 2 trial presented in a poster at the annual meeting of the American Academy of Allergy, Asthma & Immunology in Philadelphia. 

The drug “demonstrated favorable long-term safety and durable efficacy,” reported Adil Adatia, MD, an assistant professor of medicine at the University of Alberta in Canada and director of the university’s Angioedema Centre of Reference and Excellence, and his colleagues. 

“The unmet need currently for patients with hereditary angioedema are treatments with lower burdens of administration,” Adatia told Medscape Medical News. “What's innovative about this product is the dosing interval is prolonged,” due to the YTE modification of the antibody. 

Hereditary angioedema involves dysregulation of the kallikrein-kinin system that can lead to recurrent swelling attacks. Several approved treatments currently exist to prevent these attacks, but they all require frequent dosing ranging from a daily oral treatment to a twice-weekly injection to an injection every 2-4 weeks. By contrast, navenibart is a long-acting kallikrein monoclonal antibody designed for dosing only two to four times a year. 

The ALPHA-SOLAR long-term open-label trial is an extension trial that followed participants enrolled in the ALPHA-STAR phase 1b/2 trial. ALPHA-STAR included 29 patients split into three cohorts of varying doses and frequencies: four patients received 450 mg on day 1 only; 13 patients received 600 mg on day 1 and 300 mg on day 84; and 12 patients received 600 mg on day 1 and 600 mg at month 2. The participants were followed for 6 months, and all 29 continued in the extension study.

The patients are an average of 46 years old and 55% are female. Most (79%) are White, 14% are Black, 7% are multiracial, and 3% are American Indian/Alaska Native. Most (86%) have hereditary angioedema C1INH type 1, and they had experienced an average of 20.4 attacks in the past year, on average every 2.2 months. 

In the extension trial, the first two groups of 17 total participants were assigned to dose regimen 1, of 600 mg on day 1 followed by 300 mg every 3 months. The 12 patients in the third cohort were assigned to a dose regimen of 600 mg on day 1, followed by 600 mg every 6 months, with the first five participants receiving an extra 600-mg dose on day 28 before continuing the dosing every 6 months. All the participants are being followed for 4 years, but this interim analysis included an average 12.5 months and a maximum of 24 months of follow-up. 

The participants following dose regimen 1 experienced an average 91.6% decrease in hereditary angioedema attack rates, from an average 2.29 attacks per month to 0.15 per month. The participants following dose regimen 2 experienced an average 89.9% reduction in attack rates, from an average 2.14 to 0.18 attacks per month. 

Overall average monthly attack rates for all the participants fell from 2.23 to 0.16 per month. Looking specifically at moderate-to-severe attacks, participants’ average attack rates fell from 1.26 to 0.09 per month. 

All participants experienced at least a 50% reduction in attack rate, and 94% of those receiving dose regimen 1 and 92% of those receiving dose regimen 2 experienced at least a 70% reduction in attack rate. Half of those receiving dose regimen 2 (50%) and 29% of those receiving dose regimen 1 experienced a 100% reduction in attack rate. 

One serious adverse event unrelated to treatment — invasive ductal breast carcinoma — led to discontinuation, but no serious adverse events or discontinuations occurred related to the treatment. The most common treatment-emergent adverse events were injection-site reactions, which occurred in three participants (10%). In addition, one participant experienced myalgia and one experienced dizziness.

No clinically significant changes in vital signs, ECGs, or safety labs, including activated partial thromboplastin time (aPTT), occurred, and no safety signals for navenibart were observed. 

Tina Merritt Meinholz, MD, an allergist and immunologist at Allergy & Asthma Clinic of Northwest Arkansas in Bentonville, was not involved with the research but noted how meaningful it would be for patients to have a treatment for hereditary angioedema that requires far less frequent dosing. 

Merritt Meinholz told Medscape Medical News that she has one patient who requires a dose of their medication, and therefore an IV infusion, every 3 days, “so this would be big for them.” 

“I have patients who take Takhzyro (lanadelumab) every 2 weeks to 4 weeks, depending on how well they do,” Merritt Meinholz said. “They’ve been doing this for most of their lives, and they would like to do less frequent injections.” 

A pivotal phase 3 ALPHA-ORBIT trial is evaluating navenibart in participants on a dosing schedule of every 3 months or every 6 months. 

The research was funded by BioCryst Pharmaceuticals. Adatia reported consulting fees and honoraria from BioCryst, Covis Pharma, CSL-Behring, and Takeda, and clinical trial support from Astria, BioCryst, Ionis Pharmaceuticals, KalVista, Octapharma, and Pharvaris. Meinholz is a coinventor on a patent for detecting IgE antibodies to alpha-gal, has served on the advisory board for some hereditary angioedema medications, and reported speakers’ fees from several pharmaceutical companies which she donates to her nonprofit White Cell Inc; she also serves on the board of two alpha-gal support groups. 

Tara Haelle is a science/health journalist based in Dallas.