Cinryze
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Cinryze - Scientific Information

Manufacture: Shire, Inc.
Country: Canada
Condition: Hereditary Angioedema
Class: Miscellaneous coagulation modifiers
Form: Intravenous (IV), Powder
Ingredients: c1 esterase inhibitor, human, L-alanine, L-threonine, L-valine, sodium chloride, sodium citrate, sucrose, sterile water for injections

Pharmaceutical Information

Drug Substance

Proper name: CINRYZE
Chemical name: C1 inhibitor (human)
Molecular mass: approximately 105 kilodaltons (kDa)
Structural formula: C1 inhibitor consists of 478 amino acids: an N-terminal domain of 113 amino acids and a serine-proteinase inhibitor or "serpin" domain of 365 amino acids.
Physicochemical properties: Soluble single-chain glycoprotein of which carbohydrate chains account for 26% to 35% of its weight.

Product Characteristics

CINRYZE (C1 inhibitor [human]) is a sterile, stable, lyophilized preparation of C1 inhibitor derived from human plasma. CINRYZE is manufactured from human plasma purified by a combination of filtration and chromatographic procedures. The specific activity of CINRYZE is 4.0–9.0 IU/mg protein. Following reconstitution with 5 mL of Sterile Water for Injections, each vial contains approximately 500 IU of functionally active C1 inhibitor, pH 6.6–7.4, and an osmolality between 200–400 mOsmol/kg. One IU of CINRYZE corresponds to the mean quantity of C1 inhibitor present in 1 mL of normal fresh plasma.

CINRYZE, when reconstituted with 5 mL of Sterile Water for Injections, contains the following excipients: 4.1 mg/mL sodium chloride, 21 mg/mL sucrose, 2.6 mg/mL sodium citrate, 2.0 mg/mL L-Valine, 1.2 mg/mL L-Alanine, and 4.5 mg/mL L-Threonine.

Viral Inactivation

Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

CINRYZE is a highly purified, viral-inactivated, nanofiltered concentrate of human C1 inhibitor that was developed specifically to further minimize the risk of transmission of infectious agents over earlier generation C1 inhibitor products. The manufacturing process utilized to extract CINRYZE from human plasma incorporates three virus inactivation/removal steps: PEG precipitation, pasteurisation, and nanofiltration. These processes result in reduction of at least 16.7 log10 for the enveloped viruses tested (HIV, BVDV, PRV), at least 8.8 log10 for the non-enveloped viruses (HAV, CPV), and >10 log10 reduction in prion-like material.

The measures taken are considered effective for enveloped viruses such as Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV), and for the non-enveloped viruses Hepatitis A Virus (HAV) and parvovirus B19. More than 14,000 doses of CINRYZE have been administered to over 260 different patients in all completed, controlled and open-label clinical studies. All patients who were evaluated were found negative for seroconversion to parvovirus B19, Hepatitis B, Hepatitis C and HIV.

Clinical Trials

Data from one randomized, double-blind, placebo-controlled study (LEVP 2005-1/B) and one open-label study (LEVP 2006-4) demonstrated the efficacy of CINRYZE for prevention of angioedema attacks in subjects with hereditary angioedema (HAE).

CINRYZE for the Routine Prevention of HAE Attacks

Table 1. Summary of subject demographics in clinical trials of CINRYZE for prevention of HAE attacks
Study #Trial designDosage, route of
administration and
duration
Study
subjects
(n=number)
Median age
(Range)
Gender
LEVP 2005-1/BRandomized, double-blind, placebocontrolled, crossoverIV 1000 IU/Placebo (N=11)
IV Placebo/1000 Units (N=11)

Subjects were treated every 3 to 4 days for 12 weeks in both therapy periods
221000 Units/Placebo: 40.0 (14-73)

Placebo/1000 Units: 35.0 (9-64)
1000 Units/Placebo: 2 M / 9 F

Placebo/ 1000 Units: 0 M / 11 F
LEVP 2006-4Open-labelIV 1000 Units

Subjects were treated every 3 to 7 days for the study duration
14636.0 (3-82)34 M / 112 F

Study LEVP 2005-1/B used a randomized, double-blind, placebo-controlled, crossover design. Patients were screened to confirm a diagnosis of HAE and a history of at least two HAE attacks per month. 24 patients (mean age 38.5 years with a range of 9 to 73 years) were randomized to one of two treatment groups: either CINRYZE prophylaxis for 12 weeks followed by 12 weeks of placebo prophylaxis, or placebo prophylaxis for 12 weeks followed by 12 weeks of CINRYZE prophylaxis. The administration of open-label CINRYZE for treatment of HAE attacks in either period of the crossover was permitted. Two subjects dropped out (one in each arm); 22 patients crossed over into period 2 and were included in the efficacy analysis.

Patients were given blinded injections (CINRYZE or placebo) every 3 to 4 days, approximately 2 times per week. Patients recorded all angioedema symptoms daily. An attack was defined as the subject-reported indication of swelling at any location following a report of no swelling on the previous day.

The efficacy determination was based on the number of attacks during the 12 week period while receiving CINRYZE as compared to the number of attacks during the placebo treatment period.

The effectiveness of CINRYZE prophylaxis in reducing the number of HAE attacks was variable among the subjects, as shown in Table 2.

Table 2. Summary of Clinical Trial Results by Individual Subject: Efficacy Dataset (LEVP 2005-1/B)
SubjectAttacks
on
C1INH
C1INH
Period
Length
(Days)
Attacks
on
Placebo
Placebo
Period
Length
(Days)
Percent
Reduction in
Number of
Attacks
Percent
Reduction in
Attack
Frequency
1081685100%100.0%
2034796100%100.0%
30811482100%100.0%
40831480100%100.0%
5284229691%89.6%
618298689%88.3%
7281138385%84.2%
8281128583%82.5%
928198178%77.8%
1028588275%75.9%
11881208260%59.5%
121085198647%46.7%
13782149350%43.3%
14782106730%42.8%
151181178535%32.1%
161381198232%30.7%
1768088025%25.0%
181282158120%21.0%
191282148614%10.1%
206856840%1.2%
2117811682-6%-7.6%
221586885-88%-85.3%
Table 3. Summary of Clinical Trial Results by Prophylactic Therapy Period: Efficacy Dataset (LEVP 2005-1/B)
StatisticCINRYZE
(N=22)
Placebo
(N=22)
Number of AttacksMean ± SD6.1 ± 5.412.7 ± 4.8
Median (range)6 (0 - 17)13.5 (6 - 22)
GEE Analysis Results
Effect Assessedp-value
Treatment Effect<0.0001
Sequence Effect0.3347
Period Effect0.3494
Table 4. Study LEVP 2005-1/B Secondary Endpoints: Efficacy Dataset
Efficacy DatasetCINRYZE
(N=22)
Placebo
(N=22)
95% CI for
Treatment Effect
(Placebo minus
CINRYZE)
p-value a
Severity of Attacks0.0008
Mean ± SD1.3 ± 0.851.9 ± 0.350.58
Range0 - 3 b1 - 3(0.19, 0.97)
Duration of Attacks (days)0.0004
Mean ± SD2.1 ± 1.133.4 ± 1.391.23
Range0 - 4 c2 - 8(0.49, 1.96)
Days of Swelling<0.0001
Mean ± SD10.1 ± 10.7329.6 ± 16.9005-19-16
Range0 - 388 - 67(11.94, 27.06)
Number of Open-label CINRYZE
Infusions for Breakthrough Attacks
<0.0001
Mean ± SD4.7 ± 8.6615.4 ± 8.4110.68
Range0 - 362 - 34(7.09, 14.28)

a: The significance level (alpha level) used for the secondary endpoints is 0.0125, based on a post-hoc adjustment for multiplicity using the Bonferroni method.
b: Average attack severity was set to 0 when there was no attack during a therapy period.
c: Average attack duration was set to 0 when there was no attack during a therapy period.

In open-label study LEVP 2006-4, 146 subjects received CINRYZE as HAE prophylaxis for periods ranging from 8 days to approximately 32 months (median 8 months). Subjects ranged in age from three to 82 years of age; 77% were female and 23% were male, and 83% were Caucasian. Prior to enrollment, subjects reported a median monthly HAE attack rate of 3.0 (range: 0.08 -28.0); during therapy with prophylactic CINRYZE, this rate was 0.21 (range: 0-4.56), and 86% of subjects experienced an average of ≤1 attack per month. For subjects receiving CINRYZE prophylaxis for at least 1 year, the monthly attack rate per subject remained consistently low (0.34 attacks per month) relative to pre-study rates.

At enrollment, 42 subjects (28.8%) were taking regular prophylactic androgens. During the study, 23 subjects (54.8%) discontinued androgens, 6 subjects (14.3%) discontinued regular use and switched to as-needed use, 5 subjects (11.9%) reduced the androgen dose, and 8 subjects (19.0%) remained on the same dose.

Nine (9) subjects not taking androgens at entry were prescribed androgens during their participation in the study. Of these, 5 subjects were prescribed androgens for short-term prophylaxis and 4 subjects were started on regular androgens.

Pediatric Population

Prevention (LEVP 2006-4): Prior to enrollment, 23 children (age range: 3- 17) reported a median monthly HAE attack rate of 3.0 (range: 0.5-28.0). During the study while receiving prophylaxis using CINRYZE, children in the various age subgroups experienced a median monthly HAE attack rate of 0.4 (range: 0-3.4), and 87% of children reported an average of ≤1 attack per month; these results were comparable to those observed in adults.

In study LEVP 2006-4, administration of CINRYZE resulted in increases in antigenic and functional C1 inhibitor levels post-infusion compared to pre-infusion values, with similar trends observed in children and adults (see Detailed Pharmacology, Pediatric population).

Detailed Pharmacology

Pharmacodynamic Effects

Low C4 levels may be seen in patients with HAE attacks. Treatment with CINRYZE in 35 subjects showed the subsequent increase in plasma C4 levels, from an average of C4 8.1 mg/dL at baseline to C4 8.6 mg/dL, 12 hours after infusion of CINRYZE.

Complement C4 levels were also measured in a randomised, parallel-group, open-label pharmacokinetic study of CINRYZE in asymptomatic HAE subjects. The subjects received either a single intravenous dose of 1000 Units or a 1000 Units dose followed by a second dose of 1000 Units 60 minutes later.

At baseline, mean C4 complement levels were 6.5 5.39 and 8.5 6.28 mg/dL in the single-dose and double-dose groups, and increased to a maximum of 11.2 6.2 and 16.5 5.8 mg/dL, respectively. The time to maximum complement C4 concentrations was approximately 48 hours after the start of infusion, returning to near baseline levels at day 7.

Pharmacokinetics

Mean pharmacokinetic parameters for functional C1 inhibitor derived from baseline-corrected concentration data are presented in Table 5.

Table 5. Mean pharmacokinetic parameters for functional C1 inhibitor following administration of CINRYZE
ParametersSingle Dose
(1000 Units*)
Double Dose
(1000 Units dose followed by a
second 1000 Units dose 60 minutes
later)
Cbaseline (Units/mL)0.31 ± 0.20 (n = 12)0.33 ± 0.20 (n = 12)
Cmax (Units/mL)0.68 ± 0.08 (n = 12)0.85 ± 0.12 (n = 13)
Baseline-corrected Cmax (Units/mL)0.37 ± 0.15 (n=12)0.51 ± 0.19 (n=12)
tmax (hr) [median (range)][1.2 (0.3 - 26.0)] (n = 12)[2.2 (1.0 - 7.5)] (n = 13)
AUC(0-t) (Units*hr/mL)74.5 ± 30.3 (n = 12)95.9 ± 19.6 (n = 13)
Baseline-corrected AUC(0-t) (Units*hr/mL)24.5 ± 19.1 (n=12)39.1 ± 20.0 (n=12)
CL (mL/min)0.85 ± 1.07 (n = 7)1.17 ± 0.78 (n = 9)
Elimination half-life (hr)56 ± 35 (n = 7)62 ± 38 (n = 9)

n=number of subjects evaluated.
*One Unit is equal to the mean quantity of C1 inhibitor present in 1 mL of normal human plasma.

After intravenous administration of a single dose of CINRYZE to HAE subjects, the serum concentration of functional C1 inhibitor doubled within 1 to 2 hours. The maximum serum concentration (Cmax) and area under the serum concentration-time curve (AUC) appeared to increase from the single to double dose, although the increase was not dose-proportional. The mean elimination half-life of functional C1 inhibitor after administration of CINRYZE was 56 hours for a single dose and 62 hours for the double dose.

Because C1 inhibitor is an endogenous human plasma protein, it is not subject to metabolism by cytochrome P450 iso-enzymes, excretion, or pharmacokinetic drug- drug interactions exhibited by many low molecular weight compounds. No specific studies have been conducted to evaluate the pharmacokinetics of CINRYZE in patients with hepatic or renal impariment.

Pediatric Population

Functional C1 inhibitor activity was measured in children in the open-label study (see Clinical Trials). Mean increases from baseline in functional C1 inhibitor activity measured 1 hour post-dose in children 3 to <18 years of age ranged from 22% to 46% in study LEVP 2006-4 compared with 25% to 32% in adults.

Toxicology

No animal studies have been completed to evaluate the effects of CINRYZE on carcinogenesis, mutagenesis, and impairment of fertility.

Toxicology studies up to 14 days duration in animals did not identify any treatment-related toxicity. Antibodies against the human protein were produced, however, the antibodies were not characterized for neutralizing activity and did not have any impact on C1 esterase activity.

An animal study showed that a potential thrombogenic threshold for CINRYZE was identified at the dose >200 Units/kg.

In an embryofetal development study (C1 inhibitor administered during the period of organogenesis) in rats, there was no maternal or fetal toxicity at doses up to 400 Units/kg that provided an exposure similar to that in humans after a 1000 Units dose.