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).

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). is caused by either quantitative deficiencies or dysfunctional production of C1-INH, leading to uncontrolled plasma kallikrein activity, excessive release of bradykinin, and consequent angioedema. 3,4 HAE attacks most commonly affect the subcutaneous tissues of the extremities, torso, face, and genitals, and the submucosal tissues of the intestines, oropharynx, and larynx. 5 The onset of attacks is generally not predictable, and attacks with laryngeal angioedema can be life-threatening because of potential upper airway obstruction and asphyxiation. 6,7 HAE attacks can be painful and incapacitating, interfering with a patient's ability to perform daily activities. 8,9 These attacks can lead to emergency room visits and hospitalization, often with incorrect diagnoses and ineffective treatments for misdiagnosed patients. 7,10 The variable frequency of attacks, the risk of laryngeal edema, and a familial history of fatal laryngeal attacks can lead to anxiety and depression, contributing to a significant burden of disease and reduced quality of life (QoL) for patients. [11][12][13][14] Intravenously (IV) or subcutaneously (SC) administered ondemand treatments reduce the severity and duration of HAE attacks. [15][16][17] Recent treatment guidelines advise that a prophylactic treatment strategy should be considered in every patient with HAE to reduce the frequency and severity of angioedema attacks and that the decision to use long-term prophylaxis should reflect the needs of the individual patient. 17,18 Historically, prophylactic treatment options included oral attenuated androgens and antifibrinolytics.
Antifibrinolytics are not efficacious, 19 and oral attenuated androgens have numerous side effects that limit their tolerability, particularly for women and children. [20][21][22] In the past 10 years, targeted therapies including IV or SC formulations of C1-INH replacement therapy, 19,23,24 an SC plasma kallikrein inhibitor (lanadelumab), 25 and an oral plasma kallikrein inhibitor (berotralstat) 26 have been shown to substantially reduce disease activity. 25 Administration of parenteral therapies may require caregivers' or healthcare professional assistance, adding a significant treatment burden, which may be difficult for some patients, particularly pediatric patients, those with a fear of needles, or those with poor peripheral venous access. 15,16,27 Because HAE is a lifelong disease, there is a need for long-term treatment options that are efficacious, well tolerated, and have a lower treatment burden. 28 Orladeyo® (berotralstat) is an oral, once-daily, highly selective inhibitor of plasma kallikrein recently approved for prevention of angioedema attacks in adults and adolescents with HAE. 29 In the primary analysis of the phase 3, randomized, double-blind, placebocontrolled APeX-2 trial (NCT03485911), treatment with berotralstat 150 and 110 mg was shown to significantly reduce HAE attack rates compared with placebo through 24 weeks (150 mg:     Table. 31 The relationship of an AE to study drug was assessed by the investigator or medically qualified designee. TEAEs of rash were required to be assessed and reported promptly for review by the medical monitor. Patients were required to discontinue berotralstat if they had liver enzyme elevations that exceeded protocol-specified levels or met other study-specified stopping rules. Patients were instructed to take berotralstat capsules orally, once daily at the same time each day with their largest meal or within 30 min of that meal. Percent study drug compliance was based upon returned capsule count and computed as the number of capsules taken divided by the expected number of capsules � 100.

| Objectives and outcome measures
The primary objective of the study was to evaluate the long-term safety and tolerability of daily dosing of oral berotralstat in patients with HAE. Safety endpoints included the proportion of patients with TEAEs, grade 3 (severe) or 4 (life-threatening) TEAEs, treatment-emergent serious adverse events (TESAEs), discontinuations due to TEAEs, drug-related TEAEs consistent with a drug rash, and treatment-emergent grade 3 or 4 laboratory abnormalities. The secondary objectives of the study were to assess effectiveness, QoL, and patient satisfaction during long-term administration of berotralstat. Effectiveness endpoints included the number and rate of HAE attacks, the durability of response (attack-rate trend over time), the proportion of days with angioedema symptoms, the number of attacks requiring treatment, discontinuations due to lack of efficacy, severity of attacks, and patient-reported outcomes (AE-QoL, TSQM).

| Statistical analysis
All safety and effectiveness analyses were conducted for the safety population (all patients receiving ≥1 dose of study drug). Demographics, disease characteristics, compliance with study treatment, and safety endpoints were summarized by treatment group.
AEs were assessed and recorded from the time the informed consent form was signed through the end-of-study visit. TEAEs were defined as AEs that occurred on or after the initiation of study drug and up to 30 days after the last dose of study drug. Unless otherwise specified, TEAEs are reported throughout this manuscript. In this study, HAE attacks and their associated symptoms were not defined as TEAEs unless they met the criteria for a serious adverse event (SAE). Patient incidence of AEs and rate per 100 person-years of exposure (PYE) were tabulated. Clinical laboratory results were summarized using descriptive statistics. Subgroup analyses of selected safety endpoints were conducted based on latency of prior androgen use (i.e., time between discontinuing the androgen and starting berotralstat) and duration of prior androgen use. An independent data monitoring committee provided safety monitoring at prespecified intervals with additional consultation or review as needed.
For effectiveness analyses, patient-reported and programmatically adjudicated HAE attacks were analyzed by treatment group using descriptive statistics. All subsequent discussions of HAE attacks in this manuscript refer to programmatically adjudicated HAE attacks unless otherwise specified. Some patients were discontinuing other prophylactic therapies prior to entry and other patients were entering from a prior berotralstat study; therefore, no baseline attack rate was collected. For the safety population,

| Treatment-emergent AEs
The median (range) duration of exposure was 342 (11-540) days for berotralstat 150 mg and 307 (14-429) days for 110 mg.  29 days after treatment interruption without recurrence of symptoms, and the event was resolved).
The AEs or laboratory abnormalities leading to discontinuation in >1
FARKAS ET AL.
-7 of 11 berotralstat exposure. All 13 had previously used androgens. All but one of the 13 patients had stopped androgens 7 to 9 days before the first dose of berotralstat; one patient stopped androgens <2 months from the first dose of berotralstat. Patients who discontinued androgens <2 weeks before starting berotralstat were more likely to experience a TEAE of ALT elevation (25%) compared with those who had never used androgens (1%) or those who discontinued androgens ≥2 weeks prior (3%). ALT elevations were generally transient with no evidence of jaundice or synthetic dysfunction and resolved or improved during the observation period; six patients discontinued berotralstat, five patients continued berotralstat, and two patients subsequently discontinued because of an unrelated perceived lack of efficacy.

| Days with angioedema symptoms
In the entire study population, the median (range) proportion of days with angioedema symptoms was low across the treatment period

| DISCUSSION
The ongoing, open-label, phase 2, APeX-S study is a large, geographically diverse, long-term study to assess the safety and effectiveness of berotralstat in patients with HAE-C1-INH. This planned data analysis demonstrated that long-term treatment with once-daily oral berotralstat 150 or 110 mg was well tolerated.
In this study, the most common drug-related AEs across both treatment groups were abdominal pain, diarrhea, and nausea. These findings were consistent with observations from the phase 3, ran- A limitation of this study is that patients were centrally allocated to treatment rather than randomized, introducing imbalances between treatment groups across different regions with varying local patterns of care, such as differences in previous prophylactic therapy.
Another limitation is that baseline attack rates were not calculated for this study because the primary objective of this study was to assess safety; patients were allowed to enroll directly from a previous berotralstat study, while treatment-naive patients were not required to complete a prospective run-in period to measure baseline attack rate. Lastly, this study was noncomparative; efficacy was compared with placebo in the APeX-2 and APeX-J trials. 26 patients. 25 Berotralstat has the advantage of being an oral therapy with a simple daily dosing regimen and a lower treatment burden.
The current results of the APeX-S study provide important data to support the safety and tolerability of berotralstat as the first targeted oral therapy for long-term prophylaxis. To support the pivotal APeX-2 trial, the larger study population and wide geographic distribution of patients in the APeX-S trial allows for greater generalizability of results. 26 This study remains ongoing to further assess long-term safety and effectiveness of berotralstat 150 mg beyond 48 weeks of therapy.