KalVista Pharmaceuticals presented new data on sebetralstat at the Western Society of Allergy, Asthma & Immunology (WSAAI) 2025 Annual Meeting, held from February 9-13 in Waimea, Hawaii.
The findings shed light on patient adherence to long-term prophylaxis (LTP) treatments for hereditary angioedema (HAE) and highlight sebetralstat’s efficacy as an on-demand therapy.
Dr. Raffi Tachdjian of UCLA presented a US commercial claims analysis revealing that nearly 40% of HAE patients initiating LTP experienced significant gaps in prescription refills over a 12-month period, with more than half discontinuing LTP altogether.
Notably, for these patients, the frequency of on-demand treatment claims remained unchanged before and after starting LTP, suggesting persistent reliance on on-demand therapies despite initiating prophylactic treatment.
HAE is a rare genetic disorder characterized by recurrent episodes of severe swelling (angioedema) in various parts of the body, including the skin, gastrointestinal tract and airways. It is caused by a deficiency or dysfunction of the C1 inhibitor protein, leading to excessive production of bradykinin, which increases vascular permeability and triggers swelling.
Without proper treatment, HAE attacks can be painful, debilitating and potentially life-threatening, especially if they involve the airway.
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Current treatments for HAE fall into two main categories: on-demand (acute) treatments to stop an attack and LTP therapies to prevent attacks.
Current HAE treatments include on-demand therapies like C1 esterase inhibitors (Berinert, Ruconest), bradykinin B2 receptor antagonists (Firazyr [icatibant injection]) and plasma kallikrein inhibitors (Kalbitor [ecallantide]), which help stop acute attacks.
LTP therapies such as Takhzyro (lanadelumab-flyo), Orladeyo (berotralstat), Haegarda (C1 esterase inhibitor subcutaneous [human]) and Cinryze (C1 esterase inhibitor [human]) aim to reduce attack frequency.
Sebetralstat is an investigational oral plasma kallikrein inhibitor developed for the treatment of HAE, even for patients on various LTP regimens. It is currently under FDA review and, if approved, would be the first oral, on-demand HAE treatment.
Kallikrein is a serine protease enzyme that plays a key role in the kallikrein-kinin system by activating kinins, such as bradykinin, which regulate blood vessel dilation and permeability. In conditions like HAE, excessive kallikrein activity leads to overproduction of bradykinin, causing episodes of severe swelling.
The FDA has set a Prescription Drug User Fee Act (PDUFA) target date of June 17, 2025, for its review decision.
Related: Sebetralstat Gets NDA Accepted by FDA for Hereditary Angioedema
At the meeting, Dr. Marc A. Riedl from the University of California, San Diego, shared interim results from the KONFIDENT-S open-label study. Participants on LTP treated 382 HAE attacks with sebetralstat, averaging 1.7 attacks per month. Over half of these attacks involved the abdomen and/or larynx. Sebetralstat facilitated early treatment (median time of 6 minutes) and rapid symptom relief (median of 1.3 hours), demonstrating effectiveness regardless of the LTP’s mechanism of action or administration route, noted KalVista in a press release announcing the results.
“Treatment guidelines recommend that patients with HAE should consider treating all attacks regardless of LTP use and should treat attacks as early as possible,” explained Dr. Riedl. “These interim results suggest that, if approved, sebetralstat could be a safe and effective oral on-demand treatment for breakthrough attacks, regardless of severity, location or type of LTP used.”
Dr. Michael E. Manning of Allergy, Asthma and Immunology Associates, Ltd., presented findings on sebetralstat’s use in patients receiving berotralstat, an oral LTP therapy. In this subgroup, 178 attacks were treated with sebetralstat, with patients averaging 1.8 attacks per month. The median time to treatment was 20 minutes, and symptom relief was achieved in a median of 1.3 hours. Sebetralstat was well-tolerated, with no increase in gastrointestinal side effects.
The findings underscore the challenges of patient adherence to LTP therapies and highlight the need for easy and effective on-demand treatments.
“In general, patients prefer oral treatments over injectables, underscoring the strong interest in oral options for HAE,” said Dr. Manning. “These results demonstrate that sebetralstat, when used as an oral on-demand treatment for attacks occurring among patients receiving berotralstat for LTP, enabled rapid treatment and symptom improvement. If approved, sebetralstat could transform the treatment landscape for physicians and patients who prefer to manage HAE without needles.”
“Injectable on-demand treatments have side effects and logistical obstacles that hinder adequate disease control and drive an over-reliance on LTP,” said Paul Audhya, MD, MBA, chief medical officer of KalVista.
He also noted that “LTP does not, however, always yield the anticipated reductions in attacks, possibly due to adherence issues in a chronic lifelong setting.”
Sebetralstat could help in the early treatment of attacks to stop progression at an early stage and reduce morbidity, even among patients on LTP, he explained.
In June 2024, KalVista submitted a New Drug Application (NDA) to the FDA, which was accepted in September 2024.
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