Key takeaways:

• Patient Global Impression of Severity scores showed greater reduction from baseline compared with placebo.
• Mean change in composite visual analog scale scores fell by 50% within 6 hours.

SAN ANTONIO — Sebetralstat significantly reduced cumulative hereditary angioedema attack and symptom severity compared with placebo, according to data presented at the American Academy of Allergy, Asthma & Immunology Annual Meeting.

“You can see relief within the first 30 minutes or an hour, which is what you want to see in an acute attack,” Jonathan A. Bernstein, MD, FAAAAI, adjunct professor of medicine at the University of Cincinnati College of Medicine, told Healio.

“The pharmacokinetics and pharmacodynamics are quite strong,” Bernstein, who is president of the AAAAI as well, also said.

Current guidelines for hereditary angioedema (HAE) attacks recommend early, on-demand treatment to decrease symptom severity, shorten attack duration and resolve the attack rapidly, the researchers said.

Jonathan A. Bernstein

Available treatments require parenteral administration and time for medication preparation, the researchers continued, and also involves pain and discomfort associated with the injection site. Sebetralstat (KalVista Pharmaceuticals), however, is an oral plasma kallikrein inhibitor.

The phase 2 study involved adults aged 18 years and older with type I or II HAE who had experienced three or more attacks in the previous 93 days and who were not on any HAE prophylactic therapy.

Patients treated two eligible HAE attacks during the study, using a 600 mg dose of sebetralstat for the first and a placebo for a second attack more than 48 hours later (n = 34), or vice versa (n = 34). The analysis included 113 treated attacks.

The researchers assessed overall HAE attack severity with the Patient Global Impression of Severity (PGI-S) scale. They also assessed HAE attack symptom severity with a 100 mm composite VAS. The Patient Global Impression of Change (PGI-C) scale was used to assess symptom relief.

Further, the researchers conducted efficacy assessments every 30 minutes during the first 4 hours following drug administration, every hour during the next 8 hours and then every 3 hours between hours 12 and 24.

Compared with placebo, there were greater reductions in PGI-S and VAS least square mean scores during the first 12 hours after sebetralstat administration. There also was a 50% mean decrease in composite VAS scores within 6 hours of treatment with sebetralstat.

Sebetralstat led to a larger increase in PGI-C least square mean scores from baseline through hour 12 compared with placebo as well, along with improvements in cumulative symptom relief within 2 hours of administration.

Compared with placebo at hours 12 and 24, the PGI-S and VAS scores for sebetralstat additionally experienced significantly greater reductions in areas under the curve (AUC), with PGI-C scores experiencing a significantly greater increase in AUC.

For example, changes in AUC for least square mean PGI-S scores at 12 hours included –0.44 (95% CI, –0.61 to –0.27) for sebetralstat and –0.07 (95% CI, –0.24 to 0.09) for placebo (P = .0024).

Changes in AUC for least square mean composite VAS scores at 12 hours included –8.39 (95% CI, –11.97 to –4.82) for sebetralstat and –1.35 (95% CI, –4.92 to 2.23) for placebo (P = .0008).

Additionally, changes in AUC for least square mean PGI-C scores at 12 hours included 1.14 (95% CI, 0.81-1.48) for sebetralstat and 0.26 (95% CI, –0.08 to 0.6) for placebo (P = .0005).

“These are strong P values,” Bernstein told Healio. “Quite significantly, the strong separation from placebo was sustained and continuous.”

The safety profile also was good, Bernstein said.

“There were not a lot of issues. They tolerated it quite well. There weren’t a lot of gastrointestinal issues or problems of that nature,” he explained, adding that sebetralstat is only used in acute situations and not continuously.

The researchers aim to continue their work.

“We’re going to go with a larger population and try to continue to show efficacy and get approval,” Bernstein said. “There are a couple of studies that are starting up right now.”

Bernstein was optimistic about the drug’s potential, too.

“You want something that’s going to have fairly quick onset of action, that’s going to have a sustained effect, and that’s going to continue to improve,” he said. “In this situation, I think that’s what they see.”

Perspective

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Timothy Craig, DO

These results are not surprising, but they are significant since an oral rescue therapy would reduce the drug burden for patients. Sebetralstat appears less effective than C1 inhibitors in time to symptom relief, but the need for intravenous treatment increases drug burden and may decrease adherence and delay treatment.

We need to see a phase 3 study. I would look at time to first symptom relief and time to total resolution of an attack. These data would help me compare sebetralstat with intravenous C1 inhibitors and icatibant (Firazyr, Takeda). A study comparing this drug to icatibant would be very helpful in decision making as well.

An oral therapy for attacks would be welcome, but it needs to work fast and have great efficacy. I would want at least 90% efficacy and significant relief in 4 hours.

Timothy Craig, DO

Clinical Researcher, Department of Medicine, Pediatrics and Biomedical Sciences, Pennsylvania State University

Disclosures: Craig reports providing research for BioCryst Pharmaceuticals, CSL Behring, Ionis Pharmaceuticals, Pharming and Takeda; consulting for BioCryst Pharmaceuticals, BioMarin Pharmaceutical and Spark Therapeutics; and serving as a speaker for CSL Behring, Grifols and Takeda.

Perspective

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Hilary Longhurst, MA, MB BS, FRCP, PhD, FRCPath

HAE is a really disabling and sometimes fatal condition that disproportionately affects women. Angioedema can affect any part of the body, including internal organs, and it typically last 2 to 3 days if untreated. Conventional angioedema treatments such as antihistamines and corticosteroids are ineffective.

Currently, those affected need injectable treatments for acute angioedema attacks. This entails a painful subcutaneous injection, usually given into the abdominal wall, or an intravenous infusion. Having a tablet to treat these attacks would be a huge step forward and would enable attacks to be treated early, at a point where severe or disabling angioedema can be prevented.

While we don’t have direct comparisons, it looks as if the tablets will be of similar efficacy/benefit to currently available injectable medications.

As doctors, we are taught that early treatment of attacks is important to reduce severity and therefore the disability associated with the attack. Having an oral treatment option will greatly facilitate this.

We need to get the message out there to families affected by HAE and their doctors that effective treatments are available, easier treatments are on the way, and that with modern medication, we can greatly relieve the burden of this disorder.

We now need to confirm these promising findings in larger trials and to raise awareness to ensure that patients with angioedema are correctly diagnosed and have access to modern medicines.

Hilary Longhurst, MA, MB BS, FRCP, PhD, FRCPath

Consultant Clinical Immunologist at Barts Health NHS Trust

Senior Medical Officer (Immunology), Auckland District Health Board

Honorary Associate Professor, Auckland University

Disclosures: Longhurst reports consultant roles with, participating in research or educational events with, or receiving personal fees from BioCryst, CSL Behring, Intellia Therapeutics, KalVista Pharmaceuticals, Pharvaris, Pharming and Takeda, all prior to 2020.

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American Academy of Allergy, Asthma & Immunology Annual Meeting