Despite preventive treatment, HAE patients require on-demand care

In review of 58 articles, more than half of patients still had swelling attacks

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Even with long-term prophylactic, or preventive, treatment, many people with hereditary angioedema (HAE) still sometimes have swelling attacks that require on-demand treatment.

That’s according to data from a systematic review presented this week at the Asia Pacific Association of Allergy, Asthma and Clinical Immunology 2023 International Conference (APAAACI) in Singapore, in the poster, “Hereditary Angioedema Attacks in Patients Receiving Long-Term Prophylaxis: A Systematic Review.”

The work was funded by KalVista Pharmaceuticals, the developer of sebetralstat, an experimental oral therapy for treating HAE attacks on demand.

“Access to safe and effective on-demand therapy is essential for all people living with HAE, including those receiving [long-term prophylactic treatment]. Sebetralstat, an oral plasma kallikrein inhibitor in late-stage development for on-demand treatment of HAE attacks, has the potential to address this persisting unmet need,” Andrew Crockett, CEO of KalVista, said in a company press release.

HAE is marked by swelling attacks driven by the low activity of the C1-inhibitor protein.

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How effective is long-term preventive treatment?

Several treatments are available for long-term prophylaxis (LTP) of HAE attacks, including ones that administer a version of the C1-inhibitor protein (e.g., Cinryze, Berinert, and Haegarda), as well as Orladeyo (berotralstat), Takhzyro (lanadelumab), and Danocrine (danazol). Tranexamic acid is also sometimes used for LTP.

“As highlighted in HAE clinical practice guidelines, the goal of LTP is to achieve full control of disease burden,” Crockett said.

The review of the available scientific literature was intended to get a better idea of how often people with HAE on LTP have swelling attacks. It included data from 58 published articles, including results from many clinical trials that supported the various LTP therapies’ approvals.

Specific results varied between studies, but the researchers noted that over many months or years of follow-up, more than half the patients were still sometimes having attacks, with most of them requiring on-demand treatment.

“Interventional and observational study results show that patients continue to experience attacks in all anatomic locations, including potentially life-threatening laryngeal [throat] attacks,” the researchers wrote.

More patients on monoclonal antibody-based treatments like Takhzyro or the experimental therapy garadacimab were free of attacks than with other LTPs. Still, a sizable fraction of patients were still having them with all the therapies.

“This systematic review of LTP treatment studies shows that attack-free rates are lower than perceived, and therefore, substantial disease burden remains for many people living with HAE,” Crockett said.

Assessing oral therapy sebetralstat as HAE treatment

A separate presentation showed an analysis of new data collected as part of the Phase 3 KONFIDENT clinical trial (NCT05259917), an ongoing study assessing the safety and effectiveness of sebetralstat.

Clinical trials tend to disproportionately include people who are white and most participants in a recent Phase 2 trial (NCT04208412) of sebetralstat were white. This Phase 1 substudy from KONFIDENT tested the therapy’s safety and pharmacological properties in people of Japanese or Chinese ancestry to compare it to those seen in white participants.

The poster was titled, “KONFIDENT Phase 3 Trial Global Expansion: Sebetralstat Pharmacokinetics and Pharmacodynamics in Japanese and Chinese Adults.”

The substudy included 74 healthy adults. About a third reported as Japanese, another third as Chinese, and a third as white. The participants were given a single dose of sebetralstat, at 300, 600, or 1,200 mg, or a placebo.

No notable differences were observed between the different ethnicities regarding sebetralstat’s safety or pharmacological profiles.

Across all ethnic groups, the therapy led to near-complete inhibition of its target, plasma kallikrein, within about a half-hour of dosing. Plasma kallikrein is responsible for producing bradykinin, the signaling molecule whose overproduction triggers swelling in HAE.

“These findings support the continued global expansion of the KONFIDENT Phase 3 trial … to assess sebetralstat for use as on-demand treatment of HAE attacks,” the researchers wrote.