Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Other haematological agents, drugs used to treat hereditary angioedema; ATC code: B06AC02.

Mechanism of action

HAE (an autosomal dominant disease) is caused by an absence or dysfunction of C1- esterase-inhibitor. 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.

Pharmacodynamic effects

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.

Clinical efficacy and safety

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 3 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
Tranexamic
Icatibant                                   Icatibant     Placebo acid
Number of                                    Number of subjects in ITT         36            38     subjects in ITT        27            29 Population                                   Population
Controlled Clinical Study of FIRAZYR vs Tranexamic acid or Placebo: Efficacy Results FAST-2                                         FAST-1
Tranexamic
Icatibant                                      Icatibant      Placebo acid
Baseline                                       Baseline
63.7             61.5                          69.3            67.7
VAS(mm)                                        VAS(mm)
Change from                                    Change from baseline to             -41.6           -14.6  baseline to             -44.8          -23.5 4 hours                                        4 hours
Difference                                     Difference between                  -27.8 (-39.4, -16.2)  between
-23.3 (-37.1, -9.4) p = 0.002 treatments (95%               p < 0.001        treatments (95%
CI, p-value)                                   CI, p-value)
Change from                                    Change from baseline to             -54.0           -30.3  baseline to             -54.2          -42.4 12 hours                                       12 hours
Difference                                     Difference between                  -24.1 (-33.6, -14.6)  between
-15.2 (-28.6, -1.7) p = 0.028 treatments (95%               p < 0.001        treatments (95%
CI, p-value)                                   CI, p-value)
Median time to                                 Median time to onset of                                       onset of symptom relief                                 symptom relief
(hours)                                        (hours)
All episodes                                   All episodes
2.0             12.0                           2.5            4.6
(N = 74)                                       (N = 56)
Response rate                                  Response rate
(%, CI) at 4 hours                             (%, CI) at 4 hours after start of                                 after start of treatment                                      treatment
All episodes            80.0            30.6   All episodes            66.7           46.4 (N = 74)            (63.1, 91.6) (16.3, 48.1) (N = 56)             (46.0, 83.5) (27.5, 66.1) Median time to                                 Median time to onset of                                       onset of symptom relief:                                symptom relief: all symptoms                                   all symptoms
(hours):                 1.6             3.5   (hours):                 2.0            3.3 Abdominal            2.6             18.1     Abdominal             3.1            10.2 pain                     1.5             12.0  pain                     1.6            9.0 Skin swelling                                  Skin swelling
Skin pain                                      Skin pain
Median time to                                 Median time to almost complete                                almost complete symptom relief                                 symptom relief
(hours)                                        (hours)
All episodes                                   All episodes
10.0             51.0                           8.5            19.4
(N = 74)                                       (N = 56)
Median time to                                 Median time to regression of                                  regression of symptoms, by                                   symptoms, by patient (hours)                                patient (hours)
All episodes                                   All episodes
0.8             7.9                            0.8            16.9
(N = 74)                                       (N = 56)
Controlled Clinical Study of FIRAZYR vs Tranexamic acid or Placebo: Efficacy Results FAST-2                                     FAST-1
Tranexamic
Icatibant                                   Icatibant     Placebo acid
Median time to                                Median time to overall patient                               overall patient improvement, by                               improvement, by physician (hours)                             physician (hours)
All episodes                                  All episodes
1.5           6.9                           1.0          5.7
(N = 74)                                      (N = 56)

Table 4. Efficacy results for FAST-3

Efficacy Results: FAST-3; Controlled Phase -- ITT population
Endpoint                      Statistic      Firazyr          Placebo          p-value (n = 43)          (n=45)
Primary Endpoint
Time to Onset of Symptom Median                 2.0             19.8            <0.001 Relief-- Composite VAS
(hrs)
Other Endpoints
Time to Onset of Primary      Median            1.5             18.5            < 0.001 Symptom Relief (hrs)
Change in Composite VAS Mean                  -19.74            -7.49           < 0.001 Score at 2 hrs after treatment
Change in Composite           Mean             -0.53            -0.22           < 0.001 Subject-Assessed
Symptom Score at 2 hours
Change in Composite           Mean             -0.44            -0.19           < 0.001 Investigator-Assessed
Symptom Score at 2 hours
Time to Almost Complete       Median            8.0             36.0             0.012 Symptom Relief (hrs)
Time to Subject-Assessed      Median            0.8              3.5            < 0.001 Initial Symptom
Improvement (hrs)
Time to Investigator-         Median            0.8              3.4            < 0.001 Assessed Initial Visual
Symptom Improvement
(hrs)


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.

Paediatric population
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).

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

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.

Absorption

Following subcutaneous administration, the absolute bioavailability of icatibant is 97%. The time to maximum concentration is approximately 30 minutes.

Distribution

Icatibant volume of distribution (Vss) is about 20-25 L. Plasma protein binding is 44%.
Biotransformation

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.

Elimination

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.

Special populations

Elderly
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.

Gender
Data suggest that there is no difference in the clearance between females and males after correcting for body weight.

Hepatic and Renal Impairment
Limited data suggest that icatibant exposure is not influenced by hepatic or renal impairment.

Race
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.

Paediatric population
The pharmacokinetics of icatibant were characterized in paediatric HAE patients in study HGT-FIR- 086 (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.