HAE attacks resolve faster with early sebetralstat treatment
New findings were generated from Phase 3 KONFIDENT trial
Initiating treatment with sebetralstat within a few minutes of the start of a hereditary angioedema (HAE) attack was associated with it resolving significantly faster than when treatment was delayed by more than two hours, according to new findings from the KONFIDENT Phase 3 trial.
Sebetralstat also led to a faster reduction in symptom burden than a placebo among patients whose attacks had already become moderate or severe at the time of treatment.
The findings were presented by developer Kalvista Pharmaceuticals at the recent 2024 American College of Allergy, Asthma, and Immunology annual meeting in Boston.
Sebetralstat is under regulatory review in the U.S., the European Union, and other countries. If it’s approved, it would become the first oral on-demand therapy available for HAE patients, as existing treatment options are all by injection.
“The HAE community has long sought a less invasive treatment option that combines needed efficacy with lower treatment burden,” Ben Palleiko, CEO of Kalvista, said in a company press release. “These presentations continue to demonstrate that sebetralstat has the potential to provide injectable-like efficacy in a pill.”
HAE guidelines instruct patients to treat their attacks as soon as they notice symptoms, as data shows this enables a faster recovery. Research by Kalvista has indicated, however, that many patients delay treatment for reasons that include cost, injection-related challenges, or the belief that swelling isn’t severe enough.
Treating HAE attacks early
Participants in the Phase 3 KONFIDENT trial (NCT05259917) were told to treat their attacks as soon as possible. That’s different than clinical trials of other on-demand therapies where attacks had to be at least moderate in severity to initiate treatment, according to Kalvista.
“If approved, sebetralstat will be the only on-demand treatment option that will have demonstrated the ability to enable compliance with treatment guidelines that call for early treatment of attacks,” Palleiko said.
HAE swelling attacks are driven by an excess of the molecule bradykinin. Sebetralstat is designed to inhibit the activity of kallikrein, a molecule involved in producing bradykinin, thereby lowering its levels and easing the severity and duration of swelling attacks.
KONFIDENT enrolled 136 patients with HAE types 1 or 2, ages 12 and older, who had a recent history of HAE attacks. In the study, each participant treated three separate swelling attacks — one with a low dose of sebetralstat (300 mg), one with a higher dose (600 mg), and another with a placebo, in random order.
Sebetralstat was associated with faster symptom relief and faster reduction in attack severity relative to a placebo, the results showed.
In the poster, ”Correlation of Time to Treatment with Attack Duration in the Sebetralstat KONFIDENT Phase 3 Trial,” Tim Craig, a physician at Penn State Health and a trial investigator, explored the relationship between how long it took KONFIDENT participants to administer treatment and their attack duration.
The analysis involved data from 55 of the earliest sebetralstat-treated attacks in the study, which were dosed within six minutes of the onset of symptoms, and compared them to 44 of the later-treated attacks, where sebetralstat was dosed after a delay of 140 minutes, or more than two hours.
The earlier treated attacks were more likely to still be mild by the time treatment was initiated relative to those treated later. About half of early-treated attacks were considered mild (50.9%), whereas most of late-treated attacks (56.8%) were moderate. Moreover, complete attack resolution was achieved significantly faster with earlier treatment than with late treatment.
“This is the first time in a Phase 3 on-demand trial where we can see that treating attacks within minutes versus hours has a meaningful impact on clinical outcomes,” Craig said.
Relief for moderate, severe HAE attacks
In a second poster, “Substantial Reduction of Hereditary Angioedema Attack Symptom Burden in the Sebetralstat Phase 3 KONFIDENT Trial,” William Lumry, MD, medical director of the AARA Research Center in Dallas and a trial investigator, explored sebetralstat’s ability to provide substantial relief for attacks that had already progressed to moderate in severity or worse by the time treatment was started.
Although most attacks in the study were treated relatively early — a median of 41 minutes after symptom onset — more than 50% still progressed to being moderate or worse by the time treatment was started, Lumry noted.
The analysis involved 49 such attacks treated with 300 mg sebetralstat, 52 treated with 600 mg sebetralstat, and 46 treated with placebo.
The median time to a substantial reduction in symptom burden, where symptom severity drops to mild or better for at least two consecutive timepoints, was significantly faster with either dose of sebetralstat at around five hours than with a placebo, where relief took more than 12 hours.
Overall, 75.5% of patients given the lower dose of sebetralstat and 67.3% given the higher dose achieved a substantial reduction in symptom burden within 24 hours, compared with a little over half of those on placebo (54.3%).
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