麻豆传媒

WASHINGTON -- The investigational oral drug sebetralstat provided on-demand relief during tissue swelling attacks from hereditary angioedema (HAE), a phase III study showed.

Following self-administration, time to the beginning of symptom relief was reduced from a median 6.7 hours with placebo to 1.6 hours with a 300-mg dose of the plasma kallikrein inhibitor (P<0.0001) and 1.8 hours with a 600-mg dose (P=0.0013), Paul Audhya, MD, of developer KalVista Pharmaceuticals in Cambridge, Massachusetts, reported here at the American Academy of Allergy, Asthma & Immunology annual meeting.

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

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

"One day it might be mild, the next day it might be severe," said Audhya, adding that an attack doesn't necessarily stay in the location it starts in. "Guidelines do recommend treating all of those attacks."

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

Over 70% of patients with HAE are on long-term prophylaxis, said Audhya, but having an oral option for attacks could improve treatment accessibility.

The phase III trial featured a crossover design in which HAE patients with type I (91.8%) or type II (8.2%) disease were randomized to one of six sequences of treatment, starting with one or two doses of either sebetralstat 300 mg, sebetralstat 600 mg, or placebo for the first attack before switching for subsequent attacks.

To be included, patients needed to have a confirmed HAE diagnosis with two documented attacks in the 3 months prior to enrollment. Additionally, they needed to be able to use and access an already available and conventional on-demand treatment for HAE, and needed to stay on a long-term, stable prophylaxis regimen for the 3 months before and during the trial.

The primary endpoint -- "beginning of symptom relief" -- was defined as feeling at least "a little better" on the seven-point Patient Global Impression of Change scale for at least two time points in a row in the 12 hours following the first dose of treatment, while the Patient Global Impression of Severity scale was used for the secondary endpoints.

Following screening, 136 participants were randomized, with 110 experiencing at least one attack during the trial, of whom 60% were women and the median age was 40 years old.

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 time of symptom onset, as well as any relief they received from their assigned treatments. 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 was 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 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.

Most participants (92%) were white, which may hinder the general applicability of the findings, the investigators acknowledged.

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