Dawnzera reduces HAE attacks by over 80% over 4 years, per final study data
Switching to less frequent dosing also found effective for some patients
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Use of Dawnzera (donidalorsen) — approved in the U.S. as a preventive treatment for hereditary angioedema (HAE) in patients ages 12 and older — led to sustained reductions in the rate of swelling attacks, accompanied by quality of life improvements, for as long as nearly four years among adults in a small clinical trial.
Switching to a reduced-frequency dosing regimen was also found to be effective for certain patients.
These are the final data from a Phase 2 extension study (NCT04307381) that evaluated the therapy’s long-term safety and effectiveness among 17 adults with HAE type 1 or type 2.
Specifically, the results showed that HAE attacks were cut by more than 80% among patients on an eight-week dosing regimen long term, and by more than 95% for those taking the preventive therapy every four weeks.
Some of these findings were shared at a medical meeting last year, with the full trial results now detailed in “Donidalorsen for hereditary angioedema: Long-term results from a 4-year phase 2 open-label extension study.” The study, published in the Annals of Allergy, Asthma & Immunology, was funded by Ionis Pharmaceuticals, which markets Dawnzera in the U.S.
“As HAE is a chronic, lifelong disease, the long-term durability of the efficacy and safety of prophylactic [preventive] treatments is critical,” the researchers wrote. “The results of this study support the use of [Dawnzera] for the long-term management of HAE.”
In people with this genetic disease, swelling attacks are driven by the overproduction of bradykinin, a molecule that makes blood vessels leaky. Dawnzera is a subcutaneous, or under-the-skin, injection treatment that reduces the production of prekallikrein, a precursor of an enzyme involved in bradykinin production. As a result, less bradykinin is produced, reducing swelling.
Dawnzera, which won U.S. approval last year, had been tested in a small Phase 2 clinical study (NCT04030598). It had outperformed a placebo in reducing swelling attacks, and also led to improvements in life quality among participants.
Long-term Dawnzera shown to control HAE swelling in adults
This open-label extension study involved 17 of the 20 patients who had participated in the Phase 2 study. Among them, 12 had been in the Dawnzera group and five had received the placebo. The mean age of the participants was 39, and nearly two-thirds were women. Thirteen completed the full four years of treatment in the extension study.
After 12 weeks, or about three months, of receiving a standard 80 mg dose of Dawnzera every four weeks, the patients entered a flexible dosing period in which they could reduce the dose to 80 mg every eight weeks if they remained attack-free. Participants could increase the dose to 100 mg every four weeks if their disease was not properly controlled.
Data showed that Dawnzera reduced the monthly attack rate by a mean of 97%, from 2.7 episodes at the start of the initial Phase 2 trial, or baseline, to 0.05 on treatment. Similarly, the monthly rates of moderate to severe attacks, as well as swelling attacks requiring on-demand treatment, were reduced by 97%, the researchers noted.
The median longest attack-free period was 990 days, or about 2.7 years, and patients were attack-free, on average, for 99.8% of the time.
From baseline to the flexible dosing period, patients on 80 mg every four weeks experienced a 97% reduction in monthly attacks, while those on 80 mg every eight weeks experienced an 83% reduction, the data showed.
Among the eight patients who switched to the less frequent dosing regimen, five stayed on that schedule, with two remaining completely attack-free. The one patient who escalated to 100 mg every four weeks experienced a 95% reduction in swelling attacks.
Broad improvements also seen in quality of life for patients
Among the participants, life quality was measured using the Angioedema Quality of Life (AE-QoL) questionnaire, in which lower scores indicate better quality of life. AE-QoL dropped by a mean of 21.3 points after about three years, considerably surpassing the threshold to be considered clinically meaningful, the researchers noted.
Improvements were seen in all domains: functioning, fatigue/mood, fears/shame, and nutrition. Both four-week and eight-week dosing groups experienced similar improvements, per the researchers.
The data support the option of switching to a more patient-friendly [every eight-week] dosing schedule after 12 weeks if complete disease control is achieved with [Dawnzera every four weeks].
Most treatment-emergent side effects were mild to moderate, and none were serious, the scientists noted. Seven patients (41%) experienced side effects considered related to Dawnzera, most commonly discoloration (18%), redness (12%), or reactions (12%) at the injection site.
Other side effects included dryness, skin thickening, irritation, pain, itching, or swelling at the injection site, each occurring in one person. Abdominal pain, low platelet counts, headache, and muscle injury all also affected one patient each, the data showed.
“For up to [four] years, [Dawnzera] was well tolerated with no safety signals, and monthly HAE attack rate reductions and improvements in quality of life were sustained,” the researchers wrote.
Additionally, the team noted that “the data support the option of switching to a more patient-friendly [every eight-week] dosing schedule after 12 weeks if complete disease control is achieved with [Dawnzera every four weeks].”
