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

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).

Patient perspectives on the treatment burden of injectable medication for hereditary angioedema.

Hereditary angioedema (HAE) is a rare, chronic disease characterized by debilitating swelling episodes in various parts of the body. Patients experience significant burdens related to the symptoms and management of HAE, which can affect their daily lives and reduce their overall quality of life. Prophylactic treatment options have expanded in the past decade to the benefit of patients; however, these therapies require scheduled injections, which can be painful, burdensome, and time consuming. We conducted an online survey of patients with HAE in the USA to better understand their experiences with available prophylactic medications and the associated treatment burdens. Our survey results suggest that most patients are satisfied with their current therapies but desire novel medications with a simpler route of administration and that, although most patients experience significant treatment-related burdens, they learn to cope with these challenges over time.

Caregivers' role in managing hereditary angioedema and perceptions of treatment-related burden.

Hereditary angioedema (HAE) is a rare genetic disease that results in recurrent, debilitating, and potentially life-threatening swelling episodes in the extremities, genitals, gastrointestinal tract, and upper airway. Patients can experience significant burdens related to their disease. Informal or familial caregivers often support patients with HAE and likely share in the disease-related burdens, although there are limited HAE caregiver-focused reports in the scientific literature. In the United States, we conducted an online survey of adults caring for an individual with HAE to better understand their experiences with the disease and identify psychosocial impacts of providing care for a patient with HAE. Thirty caregivers provided responses to the survey. Most caregivers were family members of the care recipient and many had HAE themselves. Caregivers reported participating in a number of medical-related tasks and experiencing some burdens as a result of caring for a person with HAE.

Physician and patient perspectives on the management of hereditary angioedema: a survey on treatment burden and needs.

Hereditary angioedema (HAE) is a rare disorder caused by genetic mutations that lead to recurrent episodes of swelling in various parts of the body. Prophylactic treatment is common for patients with HAE, and the therapeutic options have expanded in recent years. The current standard of care for prophylactic HAE therapies is subcutaneous treatment, which can be self-administered at home, greatly improving patient quality of life. As new therapies emerge, it is important for patients and physicians to discuss the risks and benefits associated with each treatment to develop an individualized approach to HAE management. We conducted surveys of patients with HAE and physicians who treat patients with HAE to identify prescribing trends for prophylactic HAE treatments and the impact that such treatments has on patients. Our results confirmed that newer, subcutaneous therapies are prescribed for HAE prophylaxis more frequently than other therapies in the United States and that treatment burdens still exist for patients with HAE. We found that physicians and patients were not always aligned on how treatment choices affect patients' lives, which may mean that there are opportunities for enhanced patient-physician dialog and shared decision-making in HAE management in the United States.

Randomized Trial of the Efficacy and Safety of Berotralstat (BCX7353) as an Oral Prophylactic Therapy for Hereditary Angioedema: Results of APeX-2 Through 48 Weeks (Part 2).

BACKGROUND: Berotralstat (BCX7353) is a recently approved, oral, once-daily kallikrein inhibitor for hereditary angioedema (HAE) prophylaxis. In the APeX-2 trial, berotralstat reduced HAE attack rates over 24 weeks, with a favorable safety and tolerability profile. OBJECTIVE: Evaluate berotralstat safety, tolerability, and effectiveness over 48 weeks. METHODS: APeX-2 is a phase 3, parallel-group, multicenter trial (NCT03485911) in patients with HAE due to C1 esterase inhibitor deficiency. Part 1 was double-blind and placebo-controlled, with patients randomized to 24 weeks of berotralstat 150 mg, 110 mg, or placebo. In part 2, patients continued berotralstat the same dose or, if initially randomized to placebo, were rerandomized to berotralstat 150 mg or 110 mg through weeks 24 to 48. The primary end point was safety and tolerability. RESULTS: One hundred eight patients received 1 or more doses of berotralstat in part 2. Treatment-emergent adverse events (TEAEs) occurred in 30 of 39 patients (77%) in the placebo group during part 1, and 25 of 34 patients (74%) re-randomized from placebo to berotralstat 110 mg or 150 mg in part 2, with drug-related TEAEs in 13 of 39 (33%), and 11 of 34 (32%) in the same groups. Most TEAEs were mild or moderate, with no serious drug-related TEAEs. The most common TEAEs were upper respiratory tract infections, abdominal pain, diarrhea, and vomiting. Mean (±standard error of the mean) monthly attack rates at baseline and week 48 were 3.06 (±0.25) and 1.06 (±0.25) in the berotralstat 150mg 48-week group and 2.97 (±0.21) and 1.35 (±0.33) in the berotralstat 110mg 48-week group. CONCLUSIONS: The safety, tolerability, and effectiveness of berotralstat were maintained over 48 weeks of treatment.

Oral berotralstat for the prophylaxis of hereditary angioedema attacks in patients in Japan: A phase 3 randomized trial.

BACKGROUND: With no approved treatments in Japan for the prevention of hereditary angioedema (HAE) attacks, there is a significant unmet need for long-term prophylactic therapies for Japanese patients with HAE. Berotralstat (BCX7353) is an oral, once-daily, highly selective inhibitor of plasma kallikrein in development for prophylaxis of angioedema attacks in HAE patients. METHODS: APeX-J is a phase 3, randomized, double-blind, placebo-controlled, parallel-group, 3-part trial conducted in Japan (University Hospital Medical Information Network identifier, UMIN000034869; ClinicalTrials.gov identifier, NCT03873116). Patients with a clinical diagnosis of type 1 or 2 HAE underwent a prospective run-in period of 56 days to determine eligibility, allowing enrollment of those with ≥2 expert-confirmed angioedema attacks. Patients were randomly assigned (1:1:1) and stratified by baseline attack rate (≥2 vs. <2 expert-confirmed attacks/month between screening and randomization) to receive once-daily berotralstat 110 mg, berotralstat 150 mg, or placebo. The primary endpoint was the rate of expert-confirmed angioedema attacks during dosing in the 24-week treatment period. RESULTS: Nineteen patients were randomized to receive once-daily berotralstat 110 mg (n = 6), berotralstat 150 mg (n = 7), or placebo (n = 6). Treatment with berotralstat 150 mg significantly reduced HAE attacks relative to placebo (1.11 vs. 2.18 attacks/month, p = .003). The most frequently reported treatment-emergent adverse events (TEAEs) in berotralstat-treated patients (n = 13) were nasopharyngitis (n = 4, 31%), abdominal pain, cough, diarrhea, and pyrexia (n = 2 each, 15%). CONCLUSIONS: Orally administered, once-daily berotralstat 150 mg significantly reduced the frequency of HAE attacks and was safe and well tolerated, supporting its use as a prophylactic therapy in patients with type 1 or 2 HAE in Japan.

Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: A randomized, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein in development for the prophylaxis of hereditary angioedema (HAE) attacks. OBJECTIVE: Our aim was to determine the efficacy, safety, and tolerability of berotralstat in patients with HAE over a 24-week treatment period (the phase 3 APeX-2 trial). METHODS: APeX-2 was a double-blind, parallel-group study that randomized patients at 40 sites in 11 countries 1:1:1 to receive once-daily berotralstat in a dose of 110 mg or 150 mg or placebo (Clinicaltrials.gov identifier NCT03485911). Patients aged 12 years or older with HAE due to C1 inhibitor deficiency and at least 2 investigator-confirmed HAE attacks in the first 56 days of a prospective run-in period were eligible. The primary efficacy end point was the rate of investigator-confirmed HAE attacks during the 24-week treatment period. RESULTS: A total of 121 patients were randomized; 120 of them received at least 1 dose of the study drug (n = 41, 40, and 39 in the 110-mg dose of berotralstat, 150-mg of dose berotralstat, and placebo groups, respectively). Berotralstat demonstrated a significant reduction in attack rate at both 110 mg (1.65 attacks per month; P = .024) and 150 mg (1.31 attacks per month; P < .001) relative to placebo (2.35 attacks per month). The most frequent treatment-emergent adverse events that occurred more with berotralstat than with placebo were abdominal pain, vomiting, diarrhea, and back pain. No drug-related serious treatment-emergent adverse events occurred. CONCLUSION: Both the 110-mg and 150-mg doses of berotralstat reduced HAE attack rates compared with placebo and were safe and generally well tolerated. The most favorable benefit-to-risk profile was observed at a dose of 150 mg per day.