Sebetralstat Can Ease Abdominal and Peripheral Attacks, Trial Reports

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by Steve Bryson, PhD |

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KalVista and sebetralstat | Angioedema News | Phase 2 trial update | illustration of swelling attack

Treatment with sebetralstat, an investigational and oral on-demand therapy, resulted in rapid relief for both abdominal and peripheral attacks in adults with hereditary angioedema (HAE), according to a new analysis Phase 2 trial data.

Sebetralstat (formerly KVD900), by KalVista Pharmaceuticals, is a small molecule inhibitor of the enzyme kallikrein, which is overly active in HAE. Overactive kallikrein gives rise to an excessive amount of an inflammatory molecule called bradykinin, which triggers sudden and severe swelling attacks.

The Phase 2 trial (NCT04208412), now completed, tested sebetralstat in 68 adults with type 1 or type 2 HAE and more than three swelling attacks in the three months before entering the study.

Its first part evaluated the pharmacokinetics of sebetralstat, or how the 600 mg dose moved into, through, and out of the body. In its second part, participants were assigned to use the therapy or a placebo to treat two swelling attacks in a random order.

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As previously reported, sebetralstat led to rapid and sustained suppression of kallikrein and was associated with fast symptom relief.

This new analysis of trial data, presented as a poster at the European Academy of Allergy and Immunology 2022 Hybrid Congress, held July 1–3 in the Czech Republic, focused on assessing the efficacy of sebetralstat in treating swelling attacks in different locations.

Of the 58 attacks treated with sebetralstat, 18 (31.0%) were categorized as abdominal and 40 (69.0%) as peripheral. Abdominal attacks included those causing abdominal symptoms, with or without peripheral symptoms, while peripheral attacks were those only causing peripheral symptoms, such as swelling and pain in the arms, legs, or genitals.

Two (11.1%) of the abdominal attacks involved both abdominal and peripheral symptoms. Peripheral attacks most commonly occurred in the arms or legs (62.5%), followed by the genitals (15.0%), and hands (12.5%).

Overall, abdominal attacks were rated as more severe than peripheral attacks before treatment (a baseline measure), as assessed by the patient global impression of change (PGI-C) scale.

Within 12 hours, sebetralstat’s use led to symptom relief in 83.3% of abdominal attacks and in 80% of peripheral attacks. The median time for symptom relief within 12 hours was slightly shorter for abdominal attacks compared with peripheral attacks (1.5 vs. 2.5 hours). Symptom relief was defined as a score of “a little better” or higher for two consecutive timepoints within 12 hours of treatment on the PGI-C scale.

Symptom improvement, defined as an improvement from baseline of one or more levels on the patient global impression of severity (PGI-S) scale within 12 hours, was seen in 66.7% of abdominal and 50% of peripheral attacks. The median time to improvement was shorter for abdominal attacks relative to peripheral attacks (2.8 vs. 10 hours).

More abdominal (61.1%) than peripheral (50.0%) attacks achieved resolution, defined as a PGI-S score of 0 (indicating “none”) within 24 hours.

Likewise, more abdominal (76.5%) than peripheral (60.6%) attacks achieved pain resolution within 24 hours based on the visual analog scale (VAS) for pain. The median time to pain resolution was six hours for abdominal attacks and 10 hours for peripheral attacks.

KalVista presented data from a population pharmacokinetic analysis of sebetralstat in healthy adults and adults with HAE in another poster.

Here, researchers found that consuming a regular meal before a single dose of sebetralstat did not alter the medication’s pharmacokinetics compared with treatment after fasting. The population model predicted that sebetralstat exposure in adolescent patients would be similar to that of adults for the 600 mg dose.

These findings supported treatment with the same doses used for adults and adolescents in the recently launched KONFIDENT Phase 3 trial (NCT05259917), which is testing sebetralstat as an on-demand treatment for swelling attacks. This study is expected to enroll at least 84 type 1 and 2 HAE patients, ages 12 and older, at sites across 20 countries; contact and information for select trial sites are available.

“The population [pharmacokinetics] study is important for our sebetralstat program,” Andrew Crockett, CEO of KalVista, said in a press release. “It expands the population we can target for treatment in our Phase 3 KONFIDENT trial without having to use multiple dose regimens.”

The company also presented preclinical data on KV998086, an oral small-molecule inhibitor of activated factor XII (FXIIa) to prevent the generation of bradykinin and deter swelling attacks in HAE.

In animal models, KV998086 blocked the generation of FXIIa and kallikrein in a dose-responsive manner, and protected mice from induced swelling. Pharmacokinetic studies showed that KV998086 displayed high oral bioavailability, or high absorption into the bloodstream when taken by mouth. These data supported KV998086 as a once-daily preventive HAE treatment that may have potential in other kallikrein-related diseases.

“The preclinical data with our oral FXIIa inhibitor once again shows the promise of this novel class of compounds, which will be important to our company’s future even beyond HAE,” Crockett said.