Long-term safety and effectiveness of berotralstat for hereditary angioedema: The open-label APeX-S study

Abstract

Background: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein recently approved for prevention of angioedema attacks in adults and adolescents with hereditary angioedema (HAE). The objective of this report is to summarize results from an interim analysis of an ongoing long-term safety study of berotralstat in patients with HAE.

Methods: APeX-S is an ongoing, phase 2, open-label study conducted in 22 countries (ClinicalTrials.gov, NCT03472040). Eligible patients with a clinical diagnosis of HAE due to C1 inhibitor deficiency (HAE-C1-INH) were centrally allocated to receive berotralstat 150 or 110 mg once daily. The primary objective was to determine long-term safety and the secondary objective was to evaluate effectiveness.

Results: Enrolled patients (N = 227) received berotralstat 150 mg (n = 127) or 110 mg (n = 100) once daily. The median (range) duration of exposure was 342 (11-540) and 307 (14-429) days for the 150-mg and 110-mg groups, respectively. Treatment-emergent adverse events (TEAEs) occurred in 91% (n = 206) of patients. The most common TEAEs across treatment groups were upper respiratory tract infection (n = 91, 40%), abdominal pain (n = 57, 25%), headache (n = 40, 18%), and diarrhea (n = 31, 14%) and were mostly mild to moderate. Fifty percent (n = 113) of patients had at least one drug-related adverse event (AE; 150 mg, n = 57 [45%]; 110 mg, n = 56 [56%]), and discontinuations due to AEs occurred in 19 (8%) patients (150 mg, n = 13 [10%]; 110 mg, n = 6 [6%]). Three (1.3%) patients experienced a drug-related serious TEAE. Among patients who received berotralstat through 48 weeks (150 mg, n = 73; 110 mg, n = 30), median HAE attack rates were low in month 1 (150 mg, 1.0 attacks/month; 110 mg, 0.5 attacks/month) and remained low through 12 months (0 attacks/month in both dose groups). Mean HAE attack rates followed a similar trend, and no evidence for patient tolerance to berotralstat emerged. In both dose groups, angioedema quality of life scores showed clinically meaningful changes from baseline.

Conclusions: In this analysis, both berotralstat doses, 150 and 110 mg once daily, were generally well tolerated. Effectiveness results support the durability and robustness of berotralstat as prophylactic therapy in patients with HAE.

Trial registration: The study is registered with ClinicalTrials.gov (NCT03472040).

Keywords: berotralstat; hereditary angioedema; long-term; prophylaxis; safety.

Conflict of interest statement

Henriette Farkas has received research grants from CSL Behring, Shire/Takeda, and Pharming; served as an advisor for CSL Behring, Shire/Takeda, Pharming, BioCryst Pharmaceuticals, and KalVista; and has participated in clinical trials/registries for BioCryst Pharmaceuticals, CSL Behring, Pharming, KalVista, and Shire/Takeda. Marcin Stobiecki reports personal fees from BioCryst during the conduct of the study; and personal fees from BioCryst, KalVista, Pharming, and Takeda (Shire) outside the submitted work. Tamar Kinaciyan reports other support from BioCryst during the conduct of the study; personal fees and grants from Shire/Takeda; and other support from CSL Behring and KalVista outside the submitted work. Marcus Maurer reports grants and personal fees from BioCryst during the conduct of the study; grants and personal fees from CSL Behring, KalVista, Shire/Takeda, and Moxie outside the submitted work; grants from Pharming; and personal fees from Pharvaris outside the submitted work. Emel Aygören‐Pürsün served as speaker for and/or advisor for and/or received grants from Adverum, BioCryst, CSL Behring, KalVista, Pharming, Pharvaris, Shire, and Takeda. Sorena Kiani‐Alikhan reports other support from BioCryst during the conduct of the study; and other support from BioCryst, Takeda, and KalVista outside the submitted work. Adrian Wu reports grants from BioCryst during the conduct of the study. Avner Reshef reports grants from BioCryst during the conduct of the study and received research grants from and served as an advisor for CSL Behring, Shire/Takeda, and Pharming. David Hagin reports other support from BioCryst during the conduct of the study. Anette Bygum has been involved in educational activities and research with the following companies: BioCryst, CSL Behring, Shire, and Takeda. Olivier Fain reports grants from BioCryst during the conduct of the study. Aarnoud Huissoon reports nonfinancial support from CSL, nonfinancial support from Biotest, and personal fees from Octapharma outside the submitted work. Miloš Jeseňák has received consultancy/speaker honoraria from CSL Behring, Shire, Sobi, and Takeda, and has served as a principal investigator for clinical trials sponsored by BioCryst, Takeda, and Pharming. Celia Zubrinich has participated in a clinical trial for BioCryst Pharmaceuticals. Karen Lindsay has received educational and research grants from Shire/Takeda. Jessica M. Best, Melanie Cornpropst, Sylvia M. Dobo, Heather A. Iocca, Bhavisha Desai, Sharon C. Murray, and William P. Sheridan are employees of BioCryst. Daniel Dix reports past employment with BioCryst. Jonny Peter, Vesna Grivcheva Panovska, and Urs C. Steiner have nothing to disclose.

Henriette Farkas, Melanie Cornpropst, and Sylvia M. Dobo contributed to the conception of the study. Henriette Farkas, Emel Aygören‐Pürsün, Melanie Cornpropst, Sylvia M. Dobo, Sharon C. Murray, Eniko Nagy, and William P. Sheridan participated in the design of the study. Henriette Farkas, Marcin Stobiecki, Jonny Peter, Tamar Kinaciyan, Marcus Maurer, Emel Aygören‐Pürsün, Sorena Kiani‐Alikhan, Adrian Wu, Avner Reshef, Anette Bygum, Olivier Fain, David Hagin, Aarnoud Huissoon, Miloš Jeseňák, Karen Lindsay, Vesna Grivcheva Panovska, Urs C. Steiner, Celia Zubrinich, Daniel Dix, Sylvia M. Dobo, Heather A. Iocca, Sharon C. Murray, and Eniko Nagy were involved with acquisition of data. Jessica M. Best, Melanie Cornpropst, Daniel Dix, Sylvia M. Dobo, Heather A. Iocca, Sharon C. Murray, Eniko Nagy, and William P. Sheridan contributed to analysis of data. Henriette Farkas, Marcin Stobiecki, Jonny Peter, Tamar Kinaciyan, Marcus Maurer, Emel Aygören‐Pürsün, Sorena Kiani‐Alikhan, Adrian Wu, Avner Reshef, Jessica M. Best, Melanie Cornpropst, Sylvia M. Dobo, Heather A. Iocca, Bhavisha Desai, Sharon C. Murray, Eniko Nagy, and William P. Sheridan participated in interpretation of data. All authors contributed to the drafting, review, and revision of the manuscript and approved the final draft.

© 2021 The Authors. Clinical and Translational Allergy published by John Wiley and Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.

Figures

FIGURE 1

Patient disposition. AE, adverse event. †Patients were centrally allocated to one of two treatment groups. At the request of the Ministry of Food and Drug Safety, patients in South Korea were randomized 1:1 between the treatment groups

FIGURE 2

Mean (A) and median (B) adjudicated monthly HAE attack rate for patients completing 48 weeks of dosing. HAE, hereditary angioedema; SEM, standard error of the mean

FIGURE 3

Plot of mean (SEM) change from baseline in AE‐QoL scores over time. AE‐QoL, Angioedema Quality of Life Questionnaire; MCID, minimum clinically important difference; SEM, standard error of the mean