Ruconest (Page 3 of 5)

12.2 Pharmacodynamics

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 U/kg of RUCONEST increases plasma C1INH activity levels to greater than 0.7 U/mL (the lower limit of normal) in HAE patients.

12.3 Pharmacokinetics

The pharmacokinetics of RUCONEST was evaluated in a study of 12 asymptomatic HAE patients (dose ranged from 6.25 U/kg to 100 U/kg). Pharmacokinetics evaluation was performed by non-compartmental analysis, using functional C1INH levels. Following administration of RUCONEST (50 U/kg) in asymptomatic HAE patients (Table 5), the mean Cmax was 1.2 U/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 U/kg.

Table 5. Baseline corrected pharmacokinetic parameters (Mean ± SD) following administration of 50 U/kg and 100 U/kg RUCONEST to asymptomatic HAE patients

Parameters

50 U/kg

100 U/kg

Cbaseline (U/mL)

0.18 ± 0.12

0.14 ± 0.08

Cmax (U/mL)

1.2 ± 0.2

2.3 ± 0.2

Tmax (hours)

0.31 ± 0.10

0.31 ± 0.10

AUC (U x hr/mL)

3.3 ± 1.0

10.6 ± 2.5

CL (mL/hr)

1207 ± 414

781 ± 147

Half-life (hours)

2.4 ± 0.6

2.7 ± 0.3

Vss (L)

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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal studies have been conducted to evaluate the effects of RUCONEST on carcinogenesis and mutagenesis. Fertility was not evaluated in animal studies.

13.2 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 U/kg) were conducted. In a 14-day monkey toxicology study of intravenous doses up to 2000 U/kg twice daily, increases in AST and ALP were observed at doses of 500 U/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 U/kg twice daily. It was concluded that the NOAEL of RUCONEST was 1000 U/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 U/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 U/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.

14 CLINICAL STUDIES

The safety and efficacy of RUCONEST for treatment of acute angioedema attacks in patients with HAE was established in Study 1, a double-blind, 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 placebo-controlled, 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 randomized studies.

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 U/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 U/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 use.

In the RCT phase, the median time to beginning of relief of symptoms was statistically significantly shorter in patients treated with RUCONEST 50 U/kg compared with patients treated with placebo as assessed by the TEQ; (Table 6, 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 U/kg N=44 Placebo N=31
Values that are not estimable are displayed as ‘- ’.

Median

90

152

95% CI

(61, 150)

(93, -)

Log-rank p-value

0.031

Figure 1. Kaplan-Meier Plot of Time to Beginning of Relief of Symptoms (Study 1, RCT Phase)

figure1
(click image for full-size original)

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 patient receiving RUCONEST as compared with patient 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 considered meaningful.

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 U/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
* Life-threatening laryngeal attacks were excluded from the randomized-controlled phase of Study 1

Attack Type*

RUCONEST 50 U/kg

n/N (%)

Placebo

n/N (%)

Abdominal

14/16 (88%)

7/12 (58%)

Facial

3/6 (50%)

0/2 (0%)

Peripheral (extremities)

17/20 (85%)

7/14 (50%)

In the OLE phase of Study 1, patients were treated with open-label RUCONEST 50 U/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 U/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 U/kg.

In Study 2 (North American RCT), patients were randomized to receive a single administration of either RUCONEST 50 U/kg (N=12), RUCONEST 100 U/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 U/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. Mean VAS scores over time with 95% Confidence Intervals (Study 2 and 3, RCT Phase)

figure-two
(click image for full-size original)

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 repeat attacks.

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