Mechanism Of Action
C1 esterase inhibitor (C1INH) is a normal constituent of
human blood and is one of the serine protease inhibitors (serpins). The primary
function of C1INH is to regulate the activation of the complement and contact
system pathways. Regulation of these systems is performed through the formation
of complexes between the protease and the inhibitor, resulting in inactivation
of both and consumption of the C1INH.
C1INH exerts its inhibitory effect by irreversibly
binding several proteases (target proteases) of the contact and complement
systems. The effect of RUCONEST on the following target proteases was assessed in
vitro: activated C1s, kallikrein, factor XIIa and factor XIa. Inhibition
kinetics were found to be comparable with those observed for plasma-derived
HAE patients have low levels of endogenous or functional
C1INH. Although the events that induce attacks of angioedema in HAE patients
are not well defined, it is thought that contact system activation, and
resulting increased vascular permeability lead to the clinical manifestation of
HAE attacks. Suppression of contact system activation by C1INH through the
inactivation of plasma kallikrein and factor XIIa is thought to modulate
vascular permeability by preventing the generation of bradykinin.5
Administration of RUCONEST increases plasma levels of
functional C1INH activity.
The complement component (protein) C4 is a substrate for
activated C1. Patients with HAE have low levels of C4 in the circulation; RUCONEST
shows a dose-dependent restoration of complement homeostasis of C4 in HAE
patients. A dose of 50 IU/kg of RUCONEST increases plasma C1INH activity levels
to greater than 0.7 IU/mL (the lower limit of normal) in HAE patients.
The pharmacokinetics of RUCONEST was evaluated in a study
of 12 asymptomatic HAE patients (dose ranged from 6.25 IU/kg to 100 IU/kg). Pharmacokinetics
evaluation was performed by non-compartmental analysis, using functional C1INH
levels. Following administration of RUCONEST (50 IU/kg) in asymptomatic HAE
patients (Table 5), the mean Cmax was 1.2 IU/mL, and the elimination half-life
was approximately 2.5 hours. The clearance of RUCONEST was nonlinear (clearance
decreased with increasing dose) over the dose range of 25-100 IU/kg.
Table 5: Baseline corrected pharmacokinetic parameters
(Mean ± SD) following administration of 50 IU/kg and 100 IU/kg RUCONEST to
asymptomatic HAE patients
||0.18 ± 0.12
||0.14 ± 0.08
||1.2 ± 0.2
||2.3 ± 0.2
||0.31 ± 0.10
||0.31 ± 0.10
|AUC (IU x hr/mL)
||3.3 ± 1.0
||10.6 ± 2.5
|Half- life (hours)
||2.4 ± 0.6
||2.7 ± 0.3
||3.0 ± 0.9
||2.4 ± 0.5
Studies have not been conducted to evaluate the PK of
RUCONEST in special patient populations, identified by race, age (pediatric or
geriatric), or the presence of renal or hepatic impairment.
Animal Toxicology And/Or Pharmacology
Single- and repeat-dose studies of up to 14 days in rats,
dogs, and cynomolgus monkeys with daily doses of RUCONEST up to 80 times the human
dose (50 IU/kg) were conducted. In a 14-day monkey toxicology study of
intravenous doses up to 2000 IU/kg twice daily, increases in AST and ALP were
observed at doses of 500 IU/kg and higher. No histopathological correlates were
observed in the liver and the increases in liver enzymes were reversible.
Histologic findings included changes in the size of thymic cortex and medulla,
and microvacuoles in the epithelial cells lining the renal tubules. The renal
tubular vacuolation was dose dependent, but was not accompanied by other
histological changes in the kidney. This finding was only partially reversible
at the highest dose level of 2000 IU/kg twice daily. It was concluded that the
NOAEL of RUCONEST was 1000 IU/kg twice daily in this species. There were no
adverse findings in a safety pharmacology study in dogs and a local tolerance
study in rabbits. It is concluded that preclinical toxicology data for daily
doses up to 40 times the proposed human dose of RUCONEST (50 IU/kg) do not indicate
a safety concern for the use of RUCONEST in humans.
Embryo-fetal studies have been conducted in rabbits and
rats at a dose of RUCONEST 12.5 times the human dose of 50 IU/kg. In rats, no malformed
fetuses were observed. In rabbits, an increase in the incidence of fetal
cardiac vessel defects was observed (1.12% [2 cases] in the treatment group
compared to 0.03% in historical controls). These defects are considered to be a
chance finding, but a RUCONEST-related effect cannot be excluded.
The safety and efficacy of RUCONEST for treatment of
acute angioedema attacks in patients with HAE was established in Study 1, a
doubleblind, randomized, placebo-controlled trial (RCT) which included an
open-label extension (OLE) phase; and supported by the results of 2 additional
RCTs and 2 additional OLE studies.
Randomized, Controlled Trials
The safety and efficacy of RUCONEST in the treatment of
acute attacks in patients with hereditary angioedema were demonstrated in a
placebocontrolled, double-blind, randomized study (Study 1). Supportive
evidence of effectiveness is provided by two double-blind, randomized, placebo-controlled
studies (Studies 2 and 3). Evidence for the efficacy of repeat treatment of HAE
attacks is provided from the open-label extensions (OLE) of each of the three
Study 1 was a randomized, double-blind,
placebo-controlled trial that included an open-label extension (OLE) phase to
assess the efficacy and safety of RUCONEST 50 IU/kg in the treatment of acute
attacks in patients with HAE. Seventy-five (75) adults and adolescent patients
were randomized (3:2) to receive RUCONEST 50 IU/kg (N = 44) or placebo (N =
31). Patients ranged in age from 17 to 69 years of age; 63% were female and 37%
were male; 96% were Caucasian.
The primary efficacy endpoint was the time to beginning
of relief of symptoms, assessed using patient-reported responses to two
questions from a Treatment Effect Questionnaire (TEQ). The TEQ required
patients to assess the severity of their attack symptoms at each affected
anatomic location, using a seven-point scale (“much worse” to “much better”
[TEQ Question 1]), and whether their symptoms had begun to decrease notably
since receiving the study medication (“yes” or “no” [TEQ Question 2]). To
achieve the primary endpoint, a patient had to have a positive response to both
questions along with persistence of improvement at the next assessment time
(i.e., the same or better response).
Rescue treatment with RUCONEST was available for patients
who did not experience the beginning of relief at 4 hours after study drug administration,
or earlier to patients who experienced life-threatening oropharyngeal-laryngeal
angioedema symptoms. If a patient received a medication which could have
impacted the efficacy evaluation or open-label RUCONEST as rescue medication,
prior to achieving beginning of relief of symptoms, the time to beginning of
relief of symptoms was censored at the last assessed time prior to medication
In the RCT phase, the median time to beginning of relief
of symptoms was statistically significantly shorter in patients treated with
RUCONEST 50 IU/kg compared with patients treated with placebo as assessed by
the TEQ; (Table , Figure 1).
Table 6: Time to Beginning of Relief of Symptoms based
on questionnaire based on TEQ (Study 1, RCT Phase)
|Time to Beginning of Relief of Symptoms, minutes
||RUCONEST 50 IU/kg
||90 (61, 150)
||152 (93, -)
|Values that are not estimable are displayed as '- '.
Figure 1: Kaplan-Meier Plot of Time to Beginning of
Relief of Symptoms (Study 1, RCT Phase)
Among several planned subgroup analyses, descriptive
statistics showed that in US patients a median time to beginning of relief of
symptoms with persistence at the primary attack location (based on TEQ) was 98
minutes [95% CI:(45, 240); n=22] for those receiving RUCONEST and 90 minutes
[95% CI:(50, -); n=16] for those receiving placebo. The hazard ratio for time
to the beginning of relief of symptoms in this subpopulation was 1.20 [95% CI:
0.48 to 3.01] for patients receiving RUCONEST as compared with patients
receiving placebo. Non-US patients receiving RUCONEST had a median time to
beginning of relief of 90 minutes [95% CI: (63, 120); n=22] and non-US patients
receiving placebo had a median time to beginning of relief of 334 minutes [95%
CI: (150, -); n=15]. The hazard ratio for the non-US subgroup was 4.82 [95% CI:
1.58 to 14.72] for patients receiving RUCONEST compared to placebo.
Examination of gender subgroups suggested a larger
treatment effect in men than women. For women receiving RUCONEST, the median
time to beginning of relief was 113 minutes [95% CI: (63, 151); n=28], and for
women receiving placebo, the median time to beginning of relief was 105 minutes
[95% CI: (60, 334); n=19]. The hazard ratio for women receiving RUCONEST versus
placebo was 1.22 [95% CI: 0.60 to 2.48]. For men receiving RUCONEST, the median
time to beginning of relief was 75 minutes [95% CI: (45, 210); n=16], and for
men receiving placebo, the median time to beginning of relief was 480 minutes [95%
CI: (150, -); n=12]. The hazard ratio for men receiving RUCONEST versus placebo
was 3.94 [95% CI: 1.23 to 12.68].
No plausible biological explanations for the regional or
gender subgroup effects were found. One possible explanation is a
larger-than-expected placebo response among US women. None of the subgroup
confidence intervals were adjusted for multiplicity.
Because almost all of the patients were Caucasian and
were between 18 and 65 years of age, race and age subgroup analyses were not
Among patients who achieved relief within 4 hours, there
were 4 (27%) patients in the placebo group who had a relapse of their symptoms
within 24 hours as compared with 1 (3%) in the RUCONEST group. The proportion
of patients who received RUCONEST as rescue medication was greater in patients
randomized to placebo (13 of 31 patients; 42%) than in patients randomized to
RUCONEST (5 of 44 patients; 11%).
The efficacy of RUCONEST 50 IU/kg for different
anatomical locations of HAE attacks is summarized in Table 7.
Table 7: Proportion of patients who achieved relief
within 4 hours, by attack type
||RUCONEST 50 IU/kg
|*Life-threatening laryngeal attacks were excluded from
the randomized-controlled phase of Study 1
In the OLE phase of Study 1, patients were treated with
open-label RUCONEST 50 IU/kg for repeated attacks of HAE. Forty-four patients
who completed the RCT phase were enrolled into the OLE phase where they were
treated for a total of 170 attacks. In this phase, the median time to beginning
of relief of symptoms was 75 minutes (95% CI: 64, 90), consistent with the
results of the RCT phase of the study (Table 6). Results were also comparable
across attacks, suggesting that the efficacy of RUCONEST 50 IU/kg was
maintained over repeated attacks of HAE. In the OLE phase of Study 1, 5/170
(3%) attacks received a second dose of RUCONEST 50 IU/kg.
In Study 2 (North American RCT), patients were randomized
to receive a single administration of either RUCONEST 50 IU/kg (N=12), RUCONEST
100 IU/kg (N=13) or placebo (N=13). Patients ranged in age from 17 to 66 years
of age; 74% were female and 26% were male; and 92% were Caucasian.
In Study 3 (European RCT), patients were randomized to
receive a single administration of either RUCONEST 100 IU/kg (N=16) or placebo (N=16).
Patients ranged in age from 17 to 71 years of age: 53% were female and 47% were
male; and 100% were Caucasian.
Patients scored their symptoms using a visual analog
scale (VAS) ranging from 0-100 mm. A VAS decrease of ≥ 20 mm compared
with baseline with persistence of the improvement at two consecutive time
points was considered the onset of relief in Studies 2 and 3.
In both Study 2 and 3, the efficacy of RUCONEST in the
treatment of acute angioedema attacks was demonstrated by significantly shorter
times to beginning of relief of symptoms based on the VAS (Figure 2).
Figure 2 : MeanVAS scores over time with 95%
Confidence Intervals (Study 2 and 3, RCT Phase)
In open-label extension studies of Study 2 and 3, 119
patients were treated with RUCONEST for a total of 362 acute angioedema
attacks. As observed in Study 1, the efficacy of RUCONEST was maintained for
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