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Berinert

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Berinert

CLINICAL PHARMACOLOGY

Mechanism of Action

C1 esterase inhibitor is a normal constituent of human plasma and belongs to the group of serine protease inhibitors (serpins) that includes antithrombin III, alpha1-protease inhibitor, alpha2-antiplasmin, and heparin cofactor II. As with the other inhibitors in this group, C1 esterase inhibitor has an important inhibiting potential on several of the major cascade systems of the human body, including the complement system, the intrinsic coagulation (contact) system, the fibrinolytic system, and the coagulation cascade. Regulation of these systems is performed through the formation of complexes between the proteinase and the inhibitor, resulting in inactivation of both and consumption of the C1 esterase inhibitor. C1 esterase inhibitor, which is usually activated during the inflammatory process, inactivates its substrate by covalently binding to the reactive site. C1 esterase inhibitor is the only known inhibitor for the subcomponent of the complement component 1 (C1r), C1s, coagulation factor XIIa, and kallikrein. Additionally, C1 esterase inhibitor is the main inhibitor for coagulation factor XIa of the intrinsic coagulation cascade.

HAE patients have low levels of endogenous or functional C1 esterase inhibitor. Although the events that induce attacks of angioedema in HAE patients are not well defined, it has been postulated that increased vascular permeability and the clinical manifestation of HAE attacks may be primarily mediated through contact system activation. Suppression of contact system activation by C1 esterase inhibitor through the inactivation of plasma kallikrein and factor XIIa is thought to modulate this vascular permeability by preventing the generation of bradykinin.5

Administration of Berinert to patients with C1 esterase inhibitor deficiency replaces the missing or malfunctioning protein in patients. The plasma concentration of C1 esterase inhibitor in healthy volunteers is approximately 270 mg/L.6

Pharmacokinetics

The pharmacokinetics of Berinert were evaluated in an open-label, uncontrolled, singlecenter study in 40 subjects (35 adults and 5 children under 16 years of age) with either mild or severe HAE. All subjects received a single intravenous injection of Berinert ranging from 500 units to 1500 units. Blood samples were taken during an attack-free period at baseline and for up to 72 hours after drug administration. Pharmacokinetic parameters were estimated using non-compartmental analysis (with or without baseline adjustment).

Table 6 summarizes the pharmacokinetic parameters in 35 adult subjects with HAE.

Table 6: Pharmacokinetic Parameters of Berinert in Adult Subjects with HAE by Non-compartmental Analysis (n=35)

Parameters Unadjusted for baseline Adjusted for baseline
AUC(0-t) (hr x IU/mL)* 27.5 ± 8.5
(15.7-44.7)
12.8 ± 6.7
(3.9-34.7)
CL (mL/hr/kg) 0.60 ± 0.17
(0.34-0.96)
1.44 ± 0.67
(0.43-3.85)
V ss (mL/kg) 18.6 ± 4.9
(11.1-27.6)
35.4 ± 10.5
(14.1-56.1)
Half-life (hrs) 21.9 ± 1.7
(16.5-24.4)
18.4 ± 3.5
(7.4-22.8)
MRT (hrs) 31.5 ± 2.4
(23.7-35.2)
26.4 ± 5.0
(10.7-33.0)
AUC: Area under the curve
CL: Clearance
Vss: Volume steady state
MRT: Mean residence time
*Based on a 15 unit/kg dose. Numbers in parentheses are the range.

Table 7 summarizes the pharmacokinetic parameters in 5 pediatric subjects (ages 6 through 13) with HAE. Based on adjusted baseline, compared to adults, the half-life of Berinert was shorter and clearance was faster in this limited cohort of children. However, the clinical implication of this difference is not known.

Table 7: Pharmacokinetic Parameters of Berinert in Pediatric Subjects with HAE by Non-compartmental Analysis (n=5)

Parameters Unadjusted for baseline Adjusted for baseline
AUC(0-t) (hr x IU/mL)* 25.45 ± 5.8
(16.8-31.7)
9.78 ± 4.37
(4.1-15.2)
CL (mL/hr/kg) 0.62 ± 0.17
(0.47-0.89)
1.9 ± 1.1
(0.98-3.69)
V ss (mL/kg) 19.8 ± 4.0
(16.7-26.1)
38.8 ± 8.9
(31.9-54.0)
Half-life (hrs) 22.4 ± 1.6
(20.3-24.4)
16.7 ± 5.8
(7.4-22.5)
MRT (hrs) 32.3 ± 2.3
(29.3-35.2)
24.0 ± 8.3
(10.7-32.4)
AUC: Area under the curve
CL: Clearance
Vss: Volume steady state
MRT: Mean residence time
*Based on a 15 unit/kg dose. Numbers in parentheses are the range.

Studies have not been conducted to evaluate the pharmacokinetics of Berinert in special patient populations identified by gender, race, geriatric age, or the presence of renal or hepatic impairment.

Animal Toxicology and/or Pharmacology

Acute intravenous toxicity of Berinert was performed in mice at 1500, 3000, and 6000 units/ kg and in rats at 1000, 2000, and 3000 units/kg. Berinert was well tolerated and no signs of toxicity were observed up to the highest dose administered.

Repeat intravenous dose toxicity was studied in a 14-day repeat dose study in rats at doses of 20, 60, and 200 units/kg/day. Berinert was well tolerated and no toxicity was observed up to the highest dose administered. No antibody response against C1 esterase inhibitor could be demonstrated in this study after multiple dosing with Berinert.

In a safety pharmacology study, Berinert was administered to beagle dogs intravenously at a cumulative dose of 3500 units/kg. No adverse effects were seen on the cardiovascular and respiratory system. There was a drop in body temperature, reduced coagulation time, and a decrease in thrombocyte aggregation.

Local intravenous tolerance of Berinert was evaluated in rabbits at 1500 units. No pathological changes were noted at the time of injection or during the following 24 hours. No pathological signs were noted during necropsy.

Thrombotic events have been reported in association with C1 esterase inhibitor products when used off-label and at higher than labeled doses1 (see OVERDOSAGE). Animal studies have confirmed the risk of thrombosis from intravenous administration of C1 esterase inhibitor products.2

Clinical Studies

The safety and efficacy of Berinert in the treatment of acute abdominal or facial attacks in subjects with hereditary angioedema were demonstrated in a placebo-controlled, double-blind, prospective, multinational, randomized, parallel-group, dose-finding, threearm, clinical study, referred to as the randomized clinical trial (RCT). The RCT assessed the efficacy and safety of Berinert in 124 adult and pediatric subjects with C1 esterase inhibitor deficiency who were experiencing an acute moderate to severe attack of abdominal or facial HAE. Subjects ranged in age from six to 72 years of age; 67.7% were female and 32.3% were male; and approximately 90% were Caucasian.

The study objectives were to evaluate whether Berinert shortens the time to onset of relief of symptoms of an abdominal or facial attack compared to placebo and to compare the efficacy of two different doses of Berinert. The time to onset of relief of symptoms was determined by the subject's response to a standard question posed at appropriate time intervals for as long as 24 hours after start of treatment, taking into account all single HAE symptoms. In addition the severity of the single HAE symptoms was assessed over time.

Subjects were randomized to receive a single 10 unit/kg body weight dose of Berinert (39 subjects), a single 20 unit/kg dose of Berinert (43 subjects), or a single dose of placebo (42 subjects) by slow intravenous infusion (recommended to be given at a rate of approximately 4 mL per minute) within 5 hours of an HAE attack. At least 70% of the subjects in each treatment group were required to be experiencing an abdominal attack.

If a subject experienced no relief or insufficient relief of symptoms by 4 hours after infusion, investigators had the option to administer a second infusion of Berinert (20 units/kg for the placebo group, 10 units/kg for the 10 units/kg group), or placebo (for the 20 units/ kg group). This masked (blinded) “rescue study medication” was administered to subjects and they were then followed until complete resolution of symptoms was achieved. Adverse events were collected for up to 7 to 9 days following the initial administration of Berinert or placebo.

In the rare case that a subject developed life-threatening laryngeal edema after inclusion into the study, immediate start of open-label treatment with a 20 unit/kg body weight dose of Berinert was allowed.

All subjects who received confounding medication (rescue medication) before symptom relief were regarded as “non-responders.” Therefore, time to onset of symptom relief was set at 24 hours if a subject received any rescue medication (ie, rescue study medication, narcotic analgesics, non-narcotic analgesics, anti-emetics, open-label C1 inhibitor, androgens at increased dose, or fresh frozen plasma) between 5 hours before administration of blinded study medication until time to onset of relief.

For the trial to be considered successful, the study protocol specified the following criteria for the differences between the Berinert 20 units/kg and the placebo group:

The time to onset of relief of symptoms of the HAE attack had to achieve a one-sided p-value of less than 0.0249 for the final analysis, and at least one of the following criteria had to demonstrate a trend in favor of Berinert with a one-sided p-value of less than 0.1:

The proportion of subjects with increased intensity of clinical HAE symptoms between 2 and 4 hours after start of treatment with study medication compared to baseline, or

The number of vomiting episodes within 4 hours after start of study treatment.

Subjects treated with 20 units/kg body weight of Berinert experienced a significant reduction (p=0.0016; “Wilcoxon Rank Sum test”) in time to onset of relief from symptoms of an HAE attack as compared to placebo (median of 48 minutes for Berinert 20 units/kg body weight, as compared to a median of > 4 hours for placebo). The time to onset of relief from symptoms of an HAE attack for subjects in the 10 unit/kg dose of Berinert was not statistically significantly different from that of subjects in the placebo group. Figure 9 is a Kaplan-Meier curve showing the percentage of subjects reporting onset of relief of HAE attack symptoms as a function of time. Individual time points beyond 4 hours are not presented on the graph, because the protocol permitted blinded rescue medication, analgesics, and/or anti-emetics to be administered starting 4 hours after randomized blinded study medication had been administered.

Figure 9: Time to Onset of Symptom Relief With Imputation to > 4 Hours for Subjects Who Received any Rescue Medication* or Non-narcotic Analgesics Before Start of Relief

Time to Onset of Symptom Relief With Imputation to > 4 Hours - Illustration

* Included rescue study medication (as blinded C1 inhibitor or placebo given as rescue medication), open-label C1 inhibitor, narcotic and non-narcotic analgesics, anti-emetics, androgens at increased dose, or fresh frozen plasma.

In addition, the efficacy of Berinert 20 units/kg body weight could be confirmed by observing a reduction in the intensity of single HAE symptoms at an earlier time compared to placebo. For abdominal attacks Figure 10a shows the time to start of relief of the last symptom to improve that was already present at baseline. Pre-defined abdominal HAE symptoms included pain, nausea, vomiting, cramps and diarrhea. Figure 10b shows the respective time to start of relief of the first symptom to improve that was already present at baseline.

Figure 10a: Time to Start of Relief of the Last Symptom to Improve (Abdominal Attacks) With Imputation to > 4 Hours for Subjects Who Received any Rescue Medication* Before Start of Relief

Time to Start of Relief of the Last Symptom to Improve (Abdominal Attacks) With Imputation to > 4 Hours - Illustration

* Included rescue study medication (as blinded C1 inhibitor or placebo given as rescue medication), open-label C1 inhibitor, narcotic and non-narcotic analgesics, anti-emetics, androgens at increased dose, or fresh frozen plasma.

Figure 10b: Time to Start of Relief of the First Symptom to Improve (Abdominal mAttacks) With Imputation to > 4 Hours for Subjects Who Received mAny Rescue Medication* Before Start of Relief

Time to Start of Relief of the First Symptom to Improve (Abdominal mAttacks) With Imputation to > 4 Hours - Illustration

* Included rescue study medication (as blinded C1 inhibitor or placebo given as rescue medication), open-label C1 inhibitor, narcotic and non-narcotic analgesics, anti-emetics, androgens at increased dose, or fresh frozen plasma.

For facial attacks, single HAE symptoms were recorded. In addition, photos were taken at pre-determined time points and assessed by the members of an independent Data Safety Monitoring Board (DSMB), who were blinded as to treatment, center and other outcome measures. The change in the severity of the edema when compared to baseline was assessed on a scale with outcomes “no change”, “better”, “worse” and “resolved”. Figure 11 shows the time to start of relief from serial facial photographs by DSMB assessment.

Figure 11: Time to Start of Relief From Serial Facial Photographs*

Time to Start of Relief From Serial Facial Photographs - Illustration

* Includes facial attacks in subjects with concomitant abdominal attacks.

Table 8 compares additional endpoints, including changes in HAE symptoms and use of rescue medication in subjects receiving Berinert at 20 units/kg body weight and placebo.

Table 8: Changes in HAE Symptoms and Use of Rescue Medication in Subjects Receiving Berinert 20 units/kg Body Weight vs. Placebo

Additional Endpoints Number (%) of Subjects Berinert 20 units/kg Body Weight Group
(n=43)
Number (%) of Subjects Placebo Group
(n=42)
Onset of symptom relief within 60 minutes after administration of study medication (post-hoc) 27
(62.8%)
11
(26.2%)
Onset of symptom relief within 4 hours after administration of study medication 30
(69.8%)
18
(42.9%)
Number of vomiting episodes within 4 hours after start of study treatment* 6 episodes 35 episodes
Worsened intensity of clinical HAE symptoms between 2 and 4 hours after administration of study medication compared to baseline† 0
(0%)
12
(28.6%)
Number (percent) of combined abdominal and facial attack subjects receiving rescue study medication, analgesics, or anti-emetics at any time prior to initial relief of symptoms 13
(30.2%)
23
(54.8%)
At least one new HAE symptom not present at baseline and starting within 4 hours after administration of study medication 2
(4.6%)
6
(14.3%)
* p-value = 0.033
† p-value = 0.00008

Both the proportion of subjects with increased intensity of clinical HAE symptoms between 2 and 4 hours after start of treatment compared to baseline, and the number of vomiting episodes within 4 hours after start of study treatment demonstrated trends in favor of Berinert in comparison to placebo (p-values < 0.1). Tables 9 through 12 present additional information regarding responses to treatment.

Table 9: Proportion of Subjects Experiencing Start of Self-Reported Relief of Symptoms by 4 Hours by Attack Type

Attack Type Berinert 20 units/kg Body Weight
(Abdominal Subjects =34)
(Facial Subjects = 9)
(Other subjects = 0)
Placebo Group
(Abdominal Subjects= 33)
(Facial Subjects = 8)
(Other subjects = 1)*
Abdominal 24 (70.6%) 15 (45.5%)
Facial 6 (66.7%) 3 (37.5%)
* Laryngeal edema initially classified as facial edema.

Table 10: Proportion of Subjects Experiencing Reduction in Severity of at Least One Individual HAE Attack Symptom by 4 Hours

Attack Type Berinert 20 units/kg Body Weight
(Abdominal Subjects = 34)
(Facial Subjects = 9)
Placebo Group
(Abdominal Subjects= 33)
(Facial Subjects = 8)
Abdominal 33 (97.1%) 29 (87.9%)
Facial 6 (66.7%) 4 (50%)

Table 11: Proportion of Subjects with Facial Attacks Demonstrating Improvement in Serial Facial Photographs by 4 hours*

Attack Type Berinert 20 units/kg Body Weight
(Subjects = 9)
Placebo Group
(Subjects = 8)
Facial 7 (77.8%) 2 (25%)
* Based on masked (blinded) evaluation by data safety monitoring board.

Table 12: Proportion of Subjects with Abdominal and Facial Attacks Receiving Rescue Study Medication at any Time Prior to Complete Relief of Symptoms

Attack Type Berinert 20 U/kg Body Weight
(Abdominal Subjects = 34)
(Facial Subjects = 9)
Placebo Group
(Abdominal Subjects= 33)
(Facial Subjects = 8)
Abdominal 7 (20.6%) 17 (51.5%)
Facial 1 (11.1%) 6 (75%)

No subjects treated with Berinert at 20 units/kg body weight reported worsening of symptoms at 4 hours after administration of study medication compared to baseline. The study demonstrated that the Berinert 20 unit/kg body weight dose was significantly more efficacious than the Berinert 10 unit/kg body weight dose or placebo.

Open-Label Extension Study

Berinert was evaluated in a prospective, open-label, uncontrolled, multicenter extension study conducted at 10 centers in the US and Canada in subjects who had participated in the RCT study for the treatment of acute abdominal or facial attacks in subjects with hereditary angioedema.

The purpose of this ongoing extension study is to provide Berinert to subjects who had participated in the RCT study and who experienced any type of subsequent HAE attack (ie, abdominal, facial, peripheral, or laryngeal).

In a non-pre-specified interim safety analysis of the ongoing open-label extension study, a total of 56 subjects (19 males and 37 females, age range: 10 to 53 years) with 559 HAE attacks treated with 20 unit/kg body weight dose of Berinert per attack, were observed at the study site until onset of relief of HAE symptoms, and were followed up for adverse events for 7 to 9 days following treatment of each HAE attack (see ADVERSE REACTIONS, Clinical Trials Experience). There were 49 subjects with abdominal attacks, 11 subjects with facial attacks, 28 subjects with peripheral attacks, and 12 subjects with laryngeal attacks.

REFERENCES

1. German Medical Profession's Drugs Committee. Severe thrombus formation of Berinert® HS. Deutsches Ärzteblatt. 2000;97:B-864.

2. Horstick G et al. Application of C1-Esterase Inhibitor During Reperfusion of Ischemic Myocardium: Dose-Related Beneficial Versus Detrimental Effects. Circulation. 2002;104:3125-3131.

3. Carrell RW, Boswell DR. Serpins: the superfamily of plasma serine proteinase inhibitors. In: Barrett A, Salvesen G, eds. Proteinase Inhibitors. Amsterdam: Elsevier. 1986;12:403-420.

4. Harrison RA. Human C1 inhibitor: Improved isolation and preliminary structural characterization. Biochemistry 1983;22:5001-5007.

5. Davis AE. The pathophysiology of hereditary angioedema. Clin Immunol. 2005; 114:3-9.

6. Nuijens JH, Eerenberg-Belmer AJM, Huijbregts CCM, et al. Proteolytic inactivation of plasma C1 inhibitor in sepsis. J Clin Invest. 1989;84:443-450.

Last reviewed on RxList: 9/15/2011
This monograph has been modified to include the generic and brand name in many instances.

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