Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Shire Pharmaceuticals Ireland Limited, Block 2 & 3 Miesian Plaza, 50 – 58 Baggot Street Lower, Dublin 2, D02 Y754, Ireland
Pharmacotherapeutic group: Other haematological agents, drugs used to treat hereditary angioedema
ATC code: B06AC02
HAE (an autosomal dominant disease) is caused by an absence or dysfunction of C1-esteraseinhibitor. HAE attacks are accompanied by an increased release of bradykinin, which is the key mediator in the development of the clinical symptoms.
HAE manifests as intermittent attacks of subcutaneous and/or sub mucosal oedema involving the upper respiratory tract, the skin and the gastrointestinal tract. An attack usually lasts between 2 to 5 days.
Icatibant is a selective competitive antagonist at the bradykinin type 2 (B2) receptor. It is a synthetic decapeptide with a structure similar to bradykinin, but with 5 non-proteinogenic amino acids. In HAE increased bradykinin concentrations are the key mediator in the development of the clinical symptoms.
In healthy young subjects, icatibant administered in doses of 0.8 mg/kg over 4 hours; 1.5 mg/kg/day or 0.15 mg/kg/day for 3 days, development of bradykinin-induced hypotension, vasodilatation and reflex tachycardia was prevented. Icatibant was shown to be a competitive antagonist when the bradykinin challenge dose was increased 4-fold.
Efficacy data were obtained from an initial open-label Phase II study and from three controlled Phase III studies.
Phase III clinical studies (FAST-1 and FAST-2) were randomized, double-blind, controlled trials and had identical designs except for the comparator (one with oral tranexamic acid as the comparator and one placebo controlled). A total of 130 patients were randomized to receive either a 30 mg dose of icatibant (63 patients) or comparator (either tranexamic acid, - 38 or placebo – 29 patients). Subsequent episodes of HAE were treated in an open label extension. Patients with symptoms of laryngeal angioedema received open label treatment with icatibant. The primary efficacy endpoint was the time to onset of symptom relief using a visual analogue scale (VAS). Table 3 shows the efficacy results for these studies.
FAST-3 was a randomized, placebo-controlled, parallel-group study of 98 adult patients with a median age of 36 years. Patients were randomized to receive either icatibant 30 mg or placebo by subcutaneous injection. A subset of patients in this study experienced acute HAE attacks while receiving androgens, antifibrinolytic agents or Cl inhibitors. The primary endpoint was time to onset of symptom relief assessed using a 3-item composite visual analog score (VAS-3) consisting of assessments of skin swelling, skin pain, and abdominal pain. Table 4 shows the efficacy results for FAST-3.
In these studies, patients on icatibant had a faster median time to onset of symptom relief (2.0, 2.5 and 2.0 hours, respectively) compared to tranexamic acid (12.0 hours) and placebo (4.6 and 19.8 hours). The treatment effect of icatibant was confirmed by secondary efficacy endpoints.
In an integrated analysis of these controlled Phase III studies, the time to onset of symptom relief and time to onset of primary symptom relief were similar regardless of age group, sex, race, weight or whether or not the patient used androgens or antifibrinolytic agents.
Response was also consistent across repeated attacks in the controlled Phase III trials. A total of 237 patients were treated with 1,386 doses of 30 mg icatibant for 1,278 attacks of acute HAE. In the first 15 Firazyr treated attacks (1,114 doses for 1,030 attacks), the median times to onset of symptom relief were similar across attacks (2.0 to 2.5 hours). 92.4% of these attacks of HAE were treated with a single dose of Firazyr.
Table 3. Efficacy results for FAST-1 and FAST-2:
| Controlled Clinical Study of FIRAZYR vs Tranexamic acid or Placebo: Efficacy Results | |||||
|---|---|---|---|---|---|
| FAST-2 | FAST-1 | ||||
| icatibant | Tranexamic acid | icatibant | Placebo | ||
| Number of subjects in ITT Population | 36 | 38 | Number of subjects in ITT Population | 27 | 29 |
| Baseline VAS (mm) | 63.7 | 61.5 | Baseline VAS (mm) | 69.3 | 67.7 |
| Change from baseline to 4 hours | -41.6 | -14.6 | Change from baseline to 4 hours | -44.8 | -23.5 |
| Difference between treatments (95% CI, p-value) | -27.8 (-39.4, -16.2) p<0.001 | Difference between treatments (95% CI, p-value) | -23.3 (-37.1, -9.4) p=0.002 | ||
| Change from baseline to 12 hours | -54.0 | -30.3 | Change from baseline to 12 hours | -54.2 | -42.4 |
| Difference between treatments (95% CI, p-value) | -24.1 (-33.6, -14.6) p<0.001 | Difference between treatments (95% CI, p-value) | -15.2 (-28.6, -1.7) p=0.028 | ||
| Median time to onset of symptom relief (hours) | Median time to onset of symptom relief (hours) | ||||
| All episodes (N=74) | 2.0 | 12.0 | All episodes (N=56) | 2.5 | 4.6 |
| Response rate (%, CI) at 4 hours after start of treatment | Response rate (%, CI) at 4 hours after start of treatment | ||||
| All episodes (N=74) | 80.0 (63.1, 91.6) | 30.6 (16.3, 48.1) | All episodes (N=56) | 66.7 (46.0, 83.5) | 46.4 (27.5, 66.1) |
| Median time to onset of symptom relief: all symptoms (hours): | Median time to onset of symptom relief: all symptoms (hours): | ||||
| Abdominal pain | 1.6 | 3.5 | Abdominal pain | 2.0 | 3.3 |
| Skin swelling | 2.6 | 18.1 | Skin swelling | 3.1 | 10.2 |
| Skin pain | 1.5 | 12.0 | Skin pain | 1.6 | 9.0 |
| Median time to almost complete symptom relief (hours) | Median time to almost complete symptom relief (hours) | ||||
| All episodes (N=74) | 10.0 | 51.0 | All episodes (N=56) | 8.5 | 19.4 |
| Median time to regression of symptoms, by patient (hours) | Median time to regression of symptoms, by patient (hours) | ||||
| All episodes (N=74) | 0.8 | 7.9 | All episodes (N=56) | 0.8 | 16.9 |
| Median time to overall patient improvement, by physician (hours) | Median time to overall patient improvement, by physician (hours) | ||||
| All episodes (N=74) | 1.5 | 6.9 | All episodes (N=56) | 1.0 | 5.7 |
Table 4. Efficacy results for FAST-3:
| Efficacy Results: FAST-3; Controlled Phase – ITT population | ||||
|---|---|---|---|---|
| Endpoint | Statistic | Firazyr (n=43) | Placebo (n=45) | p-value |
| Primary Endpoint | ||||
| Time to Onset of Symptom Relief – Composite VAS (hrs) | Median | 2.0 | 19.8 | <0.001 |
| Other Endpoints | ||||
| Time to Onset of Primary Symptom Relief (hrs) | Median | 1.5 | 18.5 | <0.001 |
| Change in Composite VAS Score at 2 hrs after treatment | Mean | -19.74 | -7.49 | <0.001 |
| Change in Composite Subject-Assessed Symptom Score at 2 hours | Mean | -0.53 | -0.22 | <0.001 |
| Change in Composite Investigator-Assessed Symptom Score at 2 hours | Mean | -0.44 | -0.19 | <0.001 |
| Time to Almost Complete Symptom Relief (hrs) | Median | 8.0 | 36.0 | 0.012 |
| Time to Subject-Assessed Initial Symptom Improvement (hrs) | Median | 0.8 | 3.5 | <0.001 |
| Time to Investigator Assessed Initial Visual Symptom Improvement (hrs) | Median | 0.8 | 3.4 | <0.001 |
A total of 66 patients with attacks of HAE affecting the larynx were treated in these controlled Phase III clinical trials. The results were similar to patients with non-laryngeal attacks of HAE with respect to time to onset of symptom relief.
An open label, non-randomised single-arm study (HGT-FIR-086) was performed with a total of 32 patients. All patients received at least one dose of icatibant (0.4mg/kg body weight up to a maximum dose of 30 mg) and the majority of patients were followed up for a minimum of 6 months. Eleven patients were of prepubertal status and 21 patients were either pubertal or postpubertal.
The efficacy population consisted of 22 patients who had been treated with icatibant (11 prepubertal and 11 pubertal/postpubertal) for HAE attack.
The primary efficacy endpoint was the time to onset of symptom relief (TOSR) measured using a composite investigator-reported symptom score. Time to symptom relief was defined as the duration of time (in hours) taken for improvement of symptoms to occur by a magnitude of 20%.
Overall the median time to onset of symptom relief was 1.0 hour (95% confidence interval, 1.0-1.1 hours). At 1 and 2 hours post treatment, approximately 50% and 90% of patients experienced onset of symptom relief, respectively.
Overall, the median time to minimal symptoms (earliest time post treatment when all symptoms were either mild or absent) was 1.1 hours (95% confidence interval, 1.0-2.0 hours).
The pharmacokinetics of icatibant has been characterized by studies using both intravenous and subcutaneous administration to healthy volunteers and patients. The pharmacokinetic profile of icatibant in patients with HAE is similar to that in healthy volunteers.
Following subcutaneous administration, the absolute bioavailability of icatibant is 97%. The time to maximum concentration is approximately 30 minutes.
Icatibant volume of distribution (Vss) is about 20-25 L. Plasma protein binding is 44%.
Icatibant is extensively metabolized by proteolytic enzymes to inactive metabolites that are primarily excreted in the urine.
In vitro studies have confirmed that icatibant is not degraded by oxidative metabolic pathways and is not an inhibitor of major cytochrome P450 (CYP) isoenzymes (CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) and is not an inducer of CYP 1A2 and 3A4.
Icatibant is mainly eliminated by metabolism with less than 10% of the dose eliminated in the urine as unchanged drug. Clearance is about 15-20 l/h and independent of dose. The terminal plasma half-life is about 1-2 hours.
Data suggest an age-related decline in clearance resulting in about 50-60% higher exposure in older people (75-80 years) compared to patients aged 40 years.
Data suggest that there is no difference in the clearance between females and males after correcting for body weight.
Limited data suggest that icatibant exposure is not influenced by hepatic or renal impairment.
Information on individual race effect is limited. Available exposure data suggest no difference in the clearance between non-White (n=40) and White (n=132) subjects.
The pharmacokinetics of icatibant were characterized in paediatric HAE patients in study HGT-FIR086 (see section 5.1). Following a single subcutaneous administration (0.4 mg/kg up to a maximum of 30 mg), the time to maximum concentration is approximately 30 minutes and the terminal half-life is about 2 hours. There are no observed differences in the exposure to icatibant between HAE patients with and without an attack. Population pharmacokinetic modelling using both adult and paediatric data showed that clearance of icatibant is related to body weight with lower clearance values noted for lower body weights in the paediatric HAE population. Based on modelling for weight banded dosing, the predicted exposure to icatibant in the paediatric HAE population (see section 4.2) is lower than the observed exposure in studies conducted with adult HAE patients.
Repeated-dose studies of up to 6-months duration in rats and 9-months duration in dogs have been conducted. In both rats and dogs, there was a dose-related reduction in circulating sex hormone levels and the repeated use of icatibant reversibly delayed sexual maturation.
Maximum daily exposures defined by area under the curve (AUC) at the No Observed Adverse Effect Levels (NOAEL) in the 9-month study in dog were 2.3 times the AUC in adult humans after a subcutaneous dose of 30 mg. A NOAEL was not measurable in the rat study, however, all of the findings from that study showed either completely or partially reversible effects in treated rats. Adrenal gland hypertrophy was observed at all doses tested in rats. Adrenal gland hypertrophy was seen to reverse after cessation of icatibant treatment. The clinical relevance of the adrenal gland findings is unknown.
Icatibant had no effect on the fertility of male mice (top dose 80.8 mg/kg/day) and rats (top dose 10 mg/kg/day).
In a 2 year study to evaluate the carcinogenic potential of icatibant in rats, daily doses giving exposure levels up to approximately 2-fold that achieved after a therapeutic dose in humans had no effect on the incidence or morphology of tumours. Results do not indicate a carcinogenic potential for icatibant.
In a standard battery of in vitro and in vivo tests icatibant was not genotoxic.
Icatibant was not teratogenic when administered by SC injection during early embryonic and fetal development in rat (top dose 25 mg/kg/day) and rabbit (top dose 10 mg/kg/day). Icatibant is a potent antagonist of bradykinin and therefore, at high dose levels, treatment can have effects on the uterine implantation process and subsequent uterine stability in early pregnancy. These uterine effects also manifest in late stage pregnancy where icatibant exhibits a tocolytic effect resulting in delayed parturition in the rat, with increased fetal distress and perinatal death at high doses (10 mg/kg/day).
A 2-week subcutaneous dose range finding study in juvenile rats identified 25 mg/kg/day as a maximally tolerated dose. In the pivotal juvenile toxicity study in which sexually immature rats were treated daily with 3 mg/kg/day for 7 weeks, atrophy of testes and epididymides were observed; the observed microscopic findings were partially reversible. Similar effects of icatibant on reproductive tissue were seen in sexually mature rats and dogs. These tissue findings were consistent with reported effects on gonadotrophins and during the subsequent treatment-free period appear to be reversible.
Icatibant did not elicit any cardiac conduction change in vitro (hERG channel) or in vivo in normal dogs or in various dog models (ventricular pacing, physical exertion and coronary ligation) where no associated hemodynamic changes were observed. Icatibant has been shown to aggravate induced cardiac ischemia in several non-clinical models, although a detrimental effect has not consistently been shown in acute ischemia.
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