Investigational oral drug sebetralstat provided on-demand relief during tissue swelling attacks from hereditary angioedema: Phase 3 study

KONFIDENT is the first phase 3 trial for oral on-demand treatment in hereditary angioedema, evaluating a representative population. Safety and efficacy results were presented at the American Academy of Allergy, Asthma & Immunology annual meeting.

"Following self-administration, there was a reduction in the time to the beginning of symptom relief from a median of 6.7 hours with a placebo to 1.6 hours with a 300-mg dose of the plasma kallikrein inhibitor and 1.8 hours with a 600-mg dose," Paul Audhya, MD, of developer KalVista Pharmaceuticals in Cambridge, Massachusetts, reported in the meeting.

According to findings presented during a late-breaking session, the KONFIDENT trial met key secondary endpoints, with both sebetralstat doses leading to faster reductions in attack severity and shorter times to complete resolution.

Hereditary angioedema is characterized by either a deficiency (type 1 HAE) or dysfunction (type II HAE) of the C1 inhibitor protein, resulting in tissue-swelling episodes that are often painful and sometimes dangerous when an attack affects a patient's upper airway. Risk factors for attacks included infections and stress.

KalVista is seeking sebetralstat's approval as the first oral, on-demand therapy for HAE and recently announced that it plans to submit a new drug application to the FDA this year. A host of drugs are approved for the condition as prophylaxis or on-demand treatment, including C1 esterase inhibitors and other plasma kallikrein inhibitors, however, the currently available on-demand options require subcutaneous or intravenous administration.

KONFIDENT is an international, randomized, double-blind, placebo-controlled, 3-way cross-over, phase 3 trial that included participants >_12 years, receiving on-demand therapy with or without long-term prophylaxis. They were randomized to treat <_3 attacks of any severity or location (except severe laryngeal) with 1-2 doses of sebetralstat 300 mg, 600 mg, or placebo.

The primary endpoint was time to the beginning of symptom relief (Patient Global Impression of Change rating of at least ‘‘A Little Better’’ two-time points in a row) within 12 hours.

The key secondary endpoints included time to first decrease in severity from attack onset (>_1 level decrease on Patient Global Impression of Severity [PGI-S] two-time points in a row) within 12 hours and time to attack resolution (PGI-S rating of ‘‘None’’) within 24 hours. Efficacy analyses were based on 252 attacks (84 attacks/treatment group).

After the screening, 136 participants were randomized; 110 experienced at least one attack during the trial, of whom 60% were women, and the median age was 40. Of the 264 total attacks, 87 occurred when patients were assigned to the 300-mg dose of sebetralstat, 93 while on the 600-mg dose, and 84 while assigned placebo.

Patients digitally documented their attacks, including the time of symptom onset and relief from their assigned treatments.

The key findings of the study were as follows:

• A majority of attacks were treated within an hour of symptoms, and the most common primary attack locations were the abdomen (43%), arms/hands (29%), legs/feet (24%), and the head/face/neck (11%). Most were mild to moderate, while 17% were severe.
• Second doses of a patient's assigned medication were allowed 3 hours or more after the first dose if determined to be necessary by the patient. This occurred 38.4% of the time with the 300-mg dose of the study drug, 41.1% with the 600-mg dose, and 55.4% with the placebo.
• · Treatment-related adverse events (AEs) with sebetralstat (2.3% with the 300-mg dose and 3.2% with the 600-mg dose) were comparable with placebo (4.8%), according to the researchers.
• Serious treatment-emergent AEs occurred after one attack treated at the 300-mg sebetralstat dose (1.2%) and two attacks treated at the 600-mg dose (2.2%) versus none with placebo. One event at the 300-mg sebetralstat dose was severe.

However, the researchers acknowledged that most participants (92%) were white, which may hinder the general applicability of the findings.

Source:

American Academy of Allergy, Asthma & Immunology annual meeting