Safety, efficacy, and pharmacokinetics of icatibant treatment in Japanese pediatric patients with hereditary angioedema: A phase 3, open‐label study

We evaluated the safety, efficacy, and pharmacokinetics of subcutaneous weight‐adjusted icatibant for the treatment of acute hereditary angioedema attacks in Japanese pediatric patients. Two patients (aged 10–13 and 6–9 years) received icatibant for a total of four attacks. Each attack was abdominal and/or cutaneous and was treated with a single icatibant injection. Mild or moderate injection‐site reactions were the only adverse events reported. Time to onset of symptom relief was 0.9–1.0 h. Icatibant was rapidly absorbed, with a pharmacokinetic profile consistent with previous studies. Simulated exposure levels were consistent with non‐Japanese pediatric patients. These results support the safety and efficacy of icatibant in Japanese pediatric patients.


| INTRODUC TI ON
Hereditary angioedema (HAE) is a rare, life-threatening disorder characterized by unpredictable, recurrent attacks of angioedema. 1,2 typically results from a quantitative (type I) or qualitative (type II) deficiency of complement 1 esterase inhibitor (C1-INH), leading to elevated levels of bradykinin and increased vascular permeability. 2e global prevalence of HAE is estimated to be about 1 in 50 000 individuals. 2 Clinical manifestations may occur at any age but usually present during childhood or adolescence, with attacks becoming more severe at puberty. 1,22][3] In one such case, a 9-year-old boy with known C1-INH deficiency died of asphyxiation within 20 min of laryngeal edema onset. 3 date, several therapies to treat acute HAE attacks in pediatric patients have been developed 1,2 ; however, there are no approved pediatric treatments for acute HAE attacks in Japan.5][6] In Europe, icatibant is indicated for the symptomatic treatment of acute HAE attacks in both adult (aged ≥18 years) and pediatric (aged 2-17 years) patients. 4In Japan, icatibant is approved only for the treatment of adults with HAE and there are no data available on icatibant use in Japanese pediatric patients. 6is study aimed to evaluate the safety, efficacy, and pharmacokinetics (PK) of icatibant for the treatment of acute HAE attacks in Japanese pediatric patients.

| ME THODS
This was an open-label, phase 3 study conducted at three hospitals in Japan from January 15, 2021 to July 26, 2021 (NCT04654351).
It was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, and applicable local regulations.The primary endpoint was frequency and severity of treatment-emergent adverse events (AEs) and the number of patients with injection-site reactions.Patients were monitored for at least 8 h after treatment, with a follow-up safety assessment conducted after 7 days.Secondary endpoints included investigator-and patient-reported time to onset of symptom relief (TOSR), time to minimal symptoms, and time to initial symptom improvement after icatibant injection.Owing to the small sample size, no statistical tests were performed.Blood samples were collected after the first icatibant injection for an initial attack to determine plasma concentrations of icatibant and its metabolites.PK parameters were estimated using the samples collected and a previously established population PK model 7 with NONMEM software (version 7.3).Data for virtual patients with age-matched information were generated using a generalized additive modeling for location, scale, and shape approach (GAMLSS) 8 on age normative data based on published growth charts. 9,10Monte Carlo simulations were performed using R® (V4.0.5), assuming a log-normal distribution for each parameter.

| RE SULTS
Informed consent was obtained for six patients, of whom two (one male and one female) received treatment with icatibant and completed the study (Table 1).In total, icatibant was administered in four acute HAE attacks: one in patient 1 (aged 10-13 years, dose 25 mg) and three in patient 2 (aged 6-9 years, dose 15 mg).Each attack was successfully treated with a single icatibant injection.Efficacy results are shown in Table 1.For all attacks, after a single icatibant injection both TOSR and time to minimal symptoms (assessed by investigator and patient) were 0.9 h for patient 1 and 1.0 h for patient 2. Time to initial symptom improvement was reported by both investigator and patient as 0.3 h for patient 1 and 1.0 h for patient 2. No rescue medications were used during the study.
Plasma concentrations of icatibant at 0.5, 1, 2, and 4 h post first dose were 962, 856, 401, and 68.9 μg/L in patient 1 and 978, 882, 410, and 38.8 μg/L in patient 2, respectively.Concentration-time profiles for icatibant were adequately characterized by the population PK model and consistent with those observed in non-Japanese pediatric patients with HAE (Supporting Information Figure S1). 11PK parameters are shown in Table 2. Icatibant was rapidly absorbed, with a time to maximum plasma concentration of 0.6 h in both patients.Overall, area under the concentration-time curve from 0 to 6 h (AUC 0-6 ) values were consistent with those observed in Japanese adults with and without HAE.Simulated median icatibant exposure levels based on weight-banded pediatric dosing (AUC 0-6 1400 ng•h/mL, maximum plasma concentration [C max ] 805 ng/mL) were consistent with non-Japanese pediatric patients with HAE (AUC 0-6 1395 ng•h/ mL, C max 807 ng/mL; Table 3).

| DISCUSS ION
This is the first study to investigate icatibant treatment for acute HAE attacks in Japanese pediatric patients.Icatibant was administered in two patients using the weight-banded pediatric dosing regimen approved in Europe. 42][13] Other than mild or moderate injection-site reactions, no AEs were reported.
Administration of icatibant provided rapid resolution of symptoms, as judged by both investigators and patients (TOSR 0.9-1.0h).The exposure level in the present study was higher than in that study, but lower than in adult patients.The safety and efficacy results presented here suggest that weight-banded dosing is appropriate for Japanese pediatric patients.
The limitations of this study include its label and nonrandomized design, as well as the small sample size.Data were collected for only two patients, which reflects the challenges of conducting a clinical trial in this very rare disease, targeting acute attacks, in one country. 6However, in the context of previous clinical data, the findings of this study suggest consistency in response to icatibant versus adults and non-Japanese pediatric patients, [11][12][13] supporting the extrapolation of adult and non-Japanese pediatric data to Japanese pediatric patients.
In conclusion, the results of this study support the safety and efficacy of icatibant in Japanese pediatric patients with acute HAE attacks.No new safety signals were identified and administration of a single, weight-adjusted dose of icatibant led to rapid symptom relief.

TA B L E 1 (Continued)
PhD, of Oxford PharmaGenesis, Melbourne, Australia and funded by Takeda Pharmaceutical Company Limited.

CO N FLI C T O F I NTE R E S T S TATE M E NT
The protocol was approved by institutional review boards at all sites.Patients or their legal representatives provided written informed consent before participation.Eligible participants were Japanese pediatric patients (aged 2 to <18 years, body weight ≥12 kg) with type I or type II HAE and an acute attack of cutaneous, abdominal, or laryngeal edema.The planned sample size was three patients, based on comprehensive feasibility assessments of patient numbers and medical institutions in Japan, with a 6-month enrollment period.Participants received a single, subcutaneous injection of icatibant (weight-banded dosing: 12-25 kg = 10 mg, 26-40 kg = 15 mg, 41-50 kg = 20 mg, 51-65 kg = 25 mg, >65 kg = 30 mg) 4 within 12 h of symptom onset.The dose was administered in hospital by a family member under the supervision of a healthcare professional.Up to two additional injections (6 h apart) were permitted within 48 h of the initial dose if there was insufficient relief or worsening of symptoms.After the initial HAE attack, patients could receive subsequent treatment with icatibant for up to two additional acute attacks.
Injection-site reactions were experienced at first icatibant exposure in patient 1 (moderate erythema, moderate swelling, mild burning sensation) and patient 2 (mild erythema), and at second exposure in patient 2 (mild erythema and mild swelling).Patient 2 did not experience an injection-site reaction at third exposure.All reactions resolved within 4-14 h.No other AEs were reported during the study.Neither patient developed anti-icatibant antibodies and no clinically meaningful changes in reproductive hormones, 12-lead electrocardiogram findings, vital signs, or clinical laboratory values were observed.

| 1475 HIDE
et al.This treatment response was consistent with data from Japanese12 and non-Japanese13 adults with HAE (median TOSR 1.5 h [n = 8] and 1.1 h [n = 43], respectively, unpublished data calculated using the TOSR definition from the current study) and non-Japanese pediatric patients with HAE (median TOSR 1.0 h [n = 22]).11Furthermore, PK modeling and simulation analyses indicated that icatibant undergoes rapid absorption and reaches therapeutic levels in Japanese pediatric patients.Model-predicted AUC 0-6 and C max were within approximately 2% of the values predicted in non-Japanese patients of equivalent ages.A previous study in non-Japanese pediatric patients with HAE treated with icatibant 0.4 mg/kg 11 found that early effects of symptom relief occurred when AUC 0-6 and C max were in the ranges 744-2160 ng•h/mL and 177-688 ng/mL, respectively.
Abbreviations: C1-INH, complement 1 esterase inhibitor; HAE, hereditary angioedema.a Actual values not shown to prevent patient identification.One patient was male and one was female.b All patients had type I or II HAE; if no data were available on amount of C1-INH protein or specific classification, HAE type was recorded as "unclassified".c Reported by investigator (≥20% improvement with no worsening of any single component score using a 5-point symptom scale [0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe]) and patient (improvement by at least one level on the Faces Pain Scale-Revised).d Reported by investigator (symptoms mild or absent using the 5-point scale) and patient (score of 0 on Faces Pain Scale-Revised).e Reported by investigator and patient as when first improvement is noted.
[cited 2023May 11].Available from: https://www.ema.europa.TA B L E 2max , time to maximum plasma concentration.a Details of the population PK model have been described previously. 7b Data from previous studies of icatibant.TA B L E 3 a 1000 virtual b Calculated as median exposure values in Japanese patients relative to median exposure values in non-Japanese patients.