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Review

Sebetralstat: A Rapidly Acting Oral Plasma Kallikrein Inhibitor for the On-Demand Treatment of Hereditary Angioedema

by
Edward P. Feener
1,*,
Rebecca L. Davie
2,
Nivetha Murugesan
1,
Stephen J. Pethen
2,
Sally L. Hampton
2,
Michael D. Smith
1,
Paul K. Audhya
1 and
Chris M. Yea
2
1
KalVista Pharmaceuticals, Cambridge, MA 02142, USA
2
KalVista Pharmaceuticals, Porton Down SP4 0BF, UK
*
Author to whom correspondence should be addressed.
Drugs Drug Candidates 2024, 3(2), 328-341; https://doi.org/10.3390/ddc3020019
Submission received: 22 February 2024 / Revised: 29 March 2024 / Accepted: 1 April 2024 / Published: 7 April 2024
(This article belongs to the Special Issue Drugs of the Kallikrein-Kinin System)
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Abstract

Sebetralstat is a novel, potent, and selective oral plasma kallikrein inhibitor drug candidate in clinical development for the on-demand treatment of hereditary angioedema (HAE). Upon binding, sebetralstat induces a conformational change in the active site of plasma kallikrein, which contributes to its high potency (Ki 3 nM) and selectivity (>1500 fold) against other serine proteases. Its physiochemical properties promote both rapid dissolution in the stomach and rapid absorption in the upper intestine that contribute to its fast and efficient absorption. A single oral administration of sebetralstat rapidly provides near-complete inhibition of plasma kallikrein and blockade of high-molecular-weight kininogen cleavage as early as 15 min, which drives its clinical efficacy. In a phase 2 clinical trial, sebetralstat significantly reduced the time to beginning of symptom relief (p < 0.0001) with median times of 1.6 h (95% CI: 1.5–3.0) with sebetralstat versus 9.0 h (4.0–17.2) with placebo. KONFIDENT (NCT05259917) is a phase 3 clinical trial assessing the on-demand use of sebetralstat for HAE. If successful, this trial could support the approval of sebetralstat as the first noninvasive, on-demand treatment option to rapidly halt HAE attacks and provide fast symptom relief.
Keywords: plasma kallikrein; hereditary angioedema; kallikrein kinin system; bradykinin; oral treatment; plasma kallikrein inhibitor; sebetralstat plasma kallikrein; hereditary angioedema; kallikrein kinin system; bradykinin; oral treatment; plasma kallikrein inhibitor; sebetralstat
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MDPI and ACS Style

Feener, E.P.; Davie, R.L.; Murugesan, N.; Pethen, S.J.; Hampton, S.L.; Smith, M.D.; Audhya, P.K.; Yea, C.M. Sebetralstat: A Rapidly Acting Oral Plasma Kallikrein Inhibitor for the On-Demand Treatment of Hereditary Angioedema. Drugs Drug Candidates 2024, 3, 328-341. https://doi.org/10.3390/ddc3020019

AMA Style

Feener EP, Davie RL, Murugesan N, Pethen SJ, Hampton SL, Smith MD, Audhya PK, Yea CM. Sebetralstat: A Rapidly Acting Oral Plasma Kallikrein Inhibitor for the On-Demand Treatment of Hereditary Angioedema. Drugs and Drug Candidates. 2024; 3(2):328-341. https://doi.org/10.3390/ddc3020019

Chicago/Turabian Style

Feener, Edward P., Rebecca L. Davie, Nivetha Murugesan, Stephen J. Pethen, Sally L. Hampton, Michael D. Smith, Paul K. Audhya, and Chris M. Yea. 2024. "Sebetralstat: A Rapidly Acting Oral Plasma Kallikrein Inhibitor for the On-Demand Treatment of Hereditary Angioedema" Drugs and Drug Candidates 3, no. 2: 328-341. https://doi.org/10.3390/ddc3020019

APA Style

Feener, E. P., Davie, R. L., Murugesan, N., Pethen, S. J., Hampton, S. L., Smith, M. D., Audhya, P. K., & Yea, C. M. (2024). Sebetralstat: A Rapidly Acting Oral Plasma Kallikrein Inhibitor for the On-Demand Treatment of Hereditary Angioedema. Drugs and Drug Candidates, 3(2), 328-341. https://doi.org/10.3390/ddc3020019

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