An investigational oral plasma kallikrein inhibitor for
on-demand treatment of hereditary angioedema: atwo-part,
randomised, double-blind, placebo-controlled, crossover phase 2
trial

J 2023

An investigational oral plasma kallikrein inhibitor for on-demand treatment of hereditary angioedema: atwo-part, randomised, double-blind, placebo-controlled, crossover phase 2 trial

AYGOEREN-PUERSUEN, Emel, Andrea ZANICHELLI, Danny M COHN, Mauro CANCIAN, Roman HAKL et. al.

Basic information

Original name

An investigational oral plasma kallikrein inhibitor for on-demand treatment of hereditary angioedema: atwo-part, randomised, double-blind, placebo-controlled, crossover phase 2 trial

Authors

AYGOEREN-PUERSUEN, Emel, Andrea ZANICHELLI, Danny M COHN, Mauro CANCIAN, Roman HAKL (203 Czech Republic, belonging to the institution), Tamar KINACIYAN, Markus MAGERL, Inmaculada MARTINEZ-SAGUER, Marcin STOBIECKI, Henriette FARKAS, Sorena KIANI-ALIKHAN, Vesna GRIVCHEVA-PANOVSKA, Jonathan A BERNSTEIN, H Henry LI, Hilary J LONGHURST, Paul K AUDHYA, Michael SMITH, Christopher M YEA, Andreas MAETZEL, Daniel K LEE, Edward P FEENER, Richard GOWER, William R LUMRY, Aleena BANERJI, Marc A RIEDL and Marcus MAURER (guarantor)

Edition

Lancet, New York, Elsevier Science Inc. 2023, 0140-6736

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30102 Immunology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 168.900 in 2022

RIV identification code

RIV/00216224:14110/23:00130695

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1016/S0140-6736(22)02406-0

UT WoS

000946727800001

Keywords in English

oral plasma kallikrein; hereditary angioedema

Abstract

V originále

Background Guidelines recommend effective on-demand therapy for all individuals with hereditary angioedema. We aimed to assess the novel oral plasma kallikrein inhibitor, sebetralstat, which is in development, for on-demand treatment of hereditary angioedema attacks. Methods In this two-part phase 2 trial, individuals with type 1 or 2 hereditary angioedema aged 18 years or older were recruited from 25 sites, consisting of specialty outpatient centres, across nine countries in Europe and the USA. Individuals were eligible if they had experienced at least three hereditary angioedema attacks in the past 93 days, were not on prophylactic therapy, and had access to and the ability to self-administer conventional attack treatment. In part 1 of the trial, participants were given a single 600 mg open-label oral dose of sebetralstat to assess safety, pharmacokinetics, and pharmacodynamics of the dose. Part 2 was a randomised, double-blind, placebo-controlled, two-sequence, two-period (2 x 2) crossover trial; participants were randomly assigned (1:1) to either sequence 1, in which they were given a single dose of 600 mg of sebetralstat to treat the first eligible attack and a second dose of placebo to treat the second eligible attack, or sequence 2, in which they were given placebo to treat the first eligible attack and then 600 mg of sebetralstat to treat the second eligible attack. Participants and investigators were masked to treatment assignment. The primary endpoint was time to use of conventional attack treatment within 12 h of study drug administration, which was assessed in all participants who were randomly assigned to treatment and who received study drug for two attacks during part 2 of the study. Safety was assessed in all participants who received at least one dose of study drug, starting in part 1. This study is registered with ClinicalTrials.gov, NCT04208412, and is completed. Findings Between July 2, 2019, and Dec 8, 2020, 84 individuals were screened and 68 were enrolled in part 1 and received sebetralstat (mean age 38middot3 years [SD 13middot2], 37 [54%] were female, 31 [46%] were male, 68 [100%] were White). 42 (62%) of 68 participants completed pharmacokinetic assessments. Sebetralstat was rapidly absorbed, with a geometric mean plasma concentration of 501 ng/mL at 15 min. In a subset of participants (n=6), plasma samples obtained from 15 min to 4 h after study drug administration had near-complete protection from ex vivo stimulated generation of plasma kallikrein and cleavage of high-molecular-weight kininogen. In part 2, all 68 participants were randomly assigned to sequence 1 (n=34) or sequence 2 (n=34). 53 (78%) of 68 participants treated two attacks (25 [74%] in the sequence 1 group and 28 [82%] in the sequence 2 group). Time to use of conventional treatment within 12 h of study drug administration was significantly longer with sebetralstat versus placebo (at quartile 1: > 12 h [95% CI 9middot6 to > 12] vs 8middot0 h [3middot8 to > 12]; p=0middot0010). There were no serious adverse events or adverse event-related discontinuations. Interpretation Oral administration of sebetralstat was well tolerated and led to rapid suppression of plasma kallikrein activity, resulting in increased time to use of conventional attack treatment and faster symptom relief versus placebo. Based on these results, a phase 3 trial to evaluate the efficacy and safety of two dose levels of sebetralstat in adolescent and adult participants with hereditary angioedema has been initiated (NCT05259917).

Citovat

AYGOEREN-PUERSUEN, Emel, Andrea ZANICHELLI, Danny M COHN, Mauro CANCIAN, Roman HAKL, Tamar KINACIYAN, Markus MAGERL, Inmaculada MARTINEZ-SAGUER, Marcin STOBIECKI, Henriette FARKAS, Sorena KIANI-ALIKHAN, Vesna GRIVCHEVA-PANOVSKA, Jonathan A BERNSTEIN, H Henry LI, Hilary J LONGHURST, Paul K AUDHYA, Michael SMITH, Christopher M YEA, Andreas MAETZEL, Daniel K LEE, Edward P FEENER, Richard GOWER, William R LUMRY, Aleena BANERJI, Marc A RIEDL and Marcus MAURER. An investigational oral plasma kallikrein inhibitor for on-demand treatment of hereditary angioedema: atwo-part, randomised, double-blind, placebo-controlled, crossover phase 2 trial. Lancet. New York: Elsevier Science Inc., 2023, vol. 401, No 10375, p. 458-469. ISSN 0140-6736. Available from: https://dx.doi.org/10.1016/S0140-6736(22)02406-0.

@article{2279451,
   author = {AygoerenandPuersuen, Emel and Zanichelli, Andrea and Cohn, Danny M and Cancian, Mauro and Hakl, Roman and Kinaciyan, Tamar and Magerl, Markus and MartinezandSaguer, Inmaculada and Stobiecki, Marcin and Farkas, Henriette and KianiandAlikhan, Sorena and GrivchevaandPanovska, Vesna and Bernstein, Jonathan A and Li, H Henry and Longhurst, Hilary J and Audhya, Paul K and Smith, Michael and Yea, Christopher M and Maetzel, Andreas and Lee, Daniel K and Feener, Edward P and Gower, Richard and Lumry, William R and Banerji, Aleena and Riedl, Marc A and Maurer, Marcus},
   article_location = {New York},
   article_number = {10375},
   doi = {http://dx.doi.org/10.1016/S0140-6736(22)02406-0},
   keywords = {oral plasma kallikrein; hereditary angioedema},
   language = {eng},
   issn = {0140-6736},
   journal = {Lancet},
   title = {An investigational oral plasma kallikrein inhibitor for on-demand treatment of hereditary angioedema: atwo-part, randomised, double-blind, placebo-controlled, crossover phase 2 trial},
   url = {https://www.sciencedirect.com/science/article/pii/S0140673622024060?via%3Dihub},
   volume = {401},
   year = {2023}
}

TY  - JOUR
ID  - 2279451
AU  - Aygoeren-Puersuen, Emel - Zanichelli, Andrea - Cohn, Danny M - Cancian, Mauro - Hakl, Roman - Kinaciyan, Tamar - Magerl, Markus - Martinez-Saguer, Inmaculada - Stobiecki, Marcin - Farkas, Henriette - Kiani-Alikhan, Sorena - Grivcheva-Panovska, Vesna - Bernstein, Jonathan A - Li, H Henry - Longhurst, Hilary J - Audhya, Paul K - Smith, Michael - Yea, Christopher M - Maetzel, Andreas - Lee, Daniel K - Feener, Edward P - Gower, Richard - Lumry, William R - Banerji, Aleena - Riedl, Marc A - Maurer, Marcus
PY  - 2023
TI  - An investigational oral plasma kallikrein inhibitor for on-demand treatment of hereditary angioedema: atwo-part, randomised, double-blind, placebo-controlled, crossover phase 2 trial
JF  - Lancet
VL  - 401
IS  - 10375
SP  - 458-469
EP  - 458-469
PB  - Elsevier Science Inc.
SN  - 01406736
KW  - oral plasma kallikrein
KW  - hereditary angioedema
UR  - https://www.sciencedirect.com/science/article/pii/S0140673622024060?via%3Dihub
N2  - Background Guidelines recommend effective on-demand therapy for all individuals with hereditary angioedema. We aimed to assess the novel oral plasma kallikrein inhibitor, sebetralstat, which is in development, for on-demand treatment of hereditary angioedema attacks. Methods In this two-part phase 2 trial, individuals with type 1 or 2 hereditary angioedema aged 18 years or older were recruited from 25 sites, consisting of specialty outpatient centres, across nine countries in Europe and the USA. Individuals were eligible if they had experienced at least three hereditary angioedema attacks in the past 93 days, were not on prophylactic therapy, and had access to and the ability to self-administer conventional attack treatment. In part 1 of the trial, participants were given a single 600 mg open-label oral dose of sebetralstat to assess safety, pharmacokinetics, and pharmacodynamics of the dose. Part 2 was a randomised, double-blind, placebo-controlled, two-sequence, two-period (2 x 2) crossover trial; participants were randomly assigned (1:1) to either sequence 1, in which they were given a single dose of 600 mg of sebetralstat to treat the first eligible attack and a second dose of placebo to treat the second eligible attack, or sequence 2, in which they were given placebo to treat the first eligible attack and then 600 mg of sebetralstat to treat the second eligible attack. Participants and investigators were masked to treatment assignment. The primary endpoint was time to use of conventional attack treatment within 12 h of study drug administration, which was assessed in all participants who were randomly assigned to treatment and who received study drug for two attacks during part 2 of the study. Safety was assessed in all participants who received at least one dose of study drug, starting in part 1. This study is registered with ClinicalTrials.gov, NCT04208412, and is completed. Findings Between July 2, 2019, and Dec 8, 2020, 84 individuals were screened and 68 were enrolled in part 1 and received sebetralstat (mean age 38middot3 years [SD 13middot2], 37 [54%] were female, 31 [46%] were male, 68 [100%] were White). 42 (62%) of 68 participants completed pharmacokinetic assessments. Sebetralstat was rapidly absorbed, with a geometric mean plasma concentration of 501 ng/mL at 15 min. In a subset of participants (n=6), plasma samples obtained from 15 min to 4 h after study drug administration had near-complete protection from ex vivo stimulated generation of plasma kallikrein and cleavage of high-molecular-weight kininogen. In part 2, all 68 participants were randomly assigned to sequence 1 (n=34) or sequence 2 (n=34). 53 (78%) of 68 participants treated two attacks (25 [74%] in the sequence 1 group and 28 [82%] in the sequence 2 group). Time to use of conventional treatment within 12 h of study drug administration was significantly longer with sebetralstat versus placebo (at quartile 1: > 12 h [95% CI 9middot6 to > 12] vs 8middot0 h [3middot8 to > 12]; p=0middot0010). There were no serious adverse events or adverse event-related discontinuations. Interpretation Oral administration of sebetralstat was well tolerated and led to rapid suppression of plasma kallikrein activity, resulting in increased time to use of conventional attack treatment and faster symptom relief versus placebo. Based on these results, a phase 3 trial to evaluate the efficacy and safety of two dose levels of sebetralstat in adolescent and adult participants with hereditary angioedema has been initiated (NCT05259917).
ER  -

AYGOEREN-PUERSUEN, Emel, Andrea ZANICHELLI, Danny M COHN, Mauro CANCIAN, Roman HAKL, Tamar KINACIYAN, Markus MAGERL, Inmaculada MARTINEZ-SAGUER, Marcin STOBIECKI, Henriette FARKAS, Sorena KIANI-ALIKHAN, Vesna GRIVCHEVA-PANOVSKA, Jonathan A BERNSTEIN, H Henry LI, Hilary J LONGHURST, Paul K AUDHYA, Michael SMITH, Christopher M YEA, Andreas MAETZEL, Daniel K LEE, Edward P FEENER, Richard GOWER, William R LUMRY, Aleena BANERJI, Marc A RIEDL and Marcus MAURER. An investigational oral plasma kallikrein inhibitor for on-demand treatment of hereditary angioedema: atwo-part, randomised, double-blind, placebo-controlled, crossover phase 2 trial. \textit{Lancet}. New York: Elsevier Science Inc., 2023, vol.~401, No~10375, p.~458-469. ISSN~0140-6736. Available from: https://dx.doi.org/10.1016/S0140-6736(22)02406-0.

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