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Alpha1-proteinase inhibitor (A1-PI) deficiency is a chronic, hereditary, autosomal, co-dominant disorder that is usually fatal in its severe form. Low blood levels of A1-PI are most commonly associated with progressive, severe emphysema that becomes clinically apparent by the third to fourth decade of life. However, an unknown percentage of individuals with severe A1-PI deficiency apparently never develop clinically evident emphysema during their lifetimes. A recent registry study showed 54% of A1-PI deficient subjects had emphysema.1 Another registry study showed 72% of A1-PI deficient subjects had pulmonary symptoms.2 Smoking is an important risk factor for the development of emphysema in patients with A1-PI deficiency. Less commonly, low blood levels of A1-PI are associated with liver disease and liver cirrhosis.3,4,5

Approximately 100 genetic variants of A1-PIdeficiency can be identified electrophoretically, only some of which are associated with the clinical disease.6,7 Ninety-five percent of A1-PI deficient individuals are of the severe PiZZ phenotype. Up to 39% of A1-PI deficient patients may have an asthmatic component to their lung disease, as evidenced by symptoms and/or bronchial hyperreactivity.1 Pulmonary infections, including pneumonia and acute bronchitis, are common in A1-PI deficient patients and contribute significantly to the morbidity of the disease.

The most direct approach to therapy for A1-PI deficiency in patients with emphysema has been to partially replace the missing protease inhibitor by intravenous infusion and, thus, attempt to ameliorate the imbalance in the anti-neutrophil elastase protection of the lower respiratory tract. Individuals with endogenous levels of A1-PI below 11 m M, in general, manifest a significantly increased risk for development of emphysema above the general population background risk.3,4,7,8 Therefore, the maintenance of blood serum levels of A1-PI (antigenically measured) above 11 m M is historically thought to provide therapeutically relevant anti-neutrophil elastase protection.9 However, the hypothesis that maintaining a serum level of antigenic A1-PI will restore protease-antiprotease balance and prevent further lung damage has never been tested in an adequately-powered controlled clinical trial.

Mechanism of Action

Pulmonary disease, particularly emphysema, is the most frequent manifestation of A1-PI deficiency.7 The pathogenesis of emphysema is understood to evolve as described in the "protease-antiprotease imbalance" model. A1-PI is now understood to be the primary antiprotease in the lower respiratory tract, where it inhibits neutrophil elastase (NE).10 Normal healthy individuals produce sufficient A1-PI to control the NE produced by activated neutrophils and are thus able to prevent inappropriate proteolysis of lung tissue by NE. Conditions that increase neutrophil accumulation and activation in the lung, such as respiratory infection and smoking, will in turn increase levels of NE. However, individuals who are severely deficient in endogenous A1-PI are unable to maintain an appropriate antiprotease defense and are thereby subject to more rapid proteolysis of the alveolar walls leading to chronic lung disease. Zemaira (alpha-proteinase inhibitor (human)) serves as A1-PI augmentation therapy in this patient population, acting to increase and maintain serum levels and lung epithelial lining fluid (ELF) levels of A1-PI.

In 18 subjects treated with a single dose (60 mg/kg) of Zemaira (alpha-proteinase inhibitor (human)) , the mean area under the curve (AUC) and standard deviation (SD) were 144 m M x day (SD 27), maximum serum concentration was 44.1 M (SD 10.8), clearance was 603 mL per day (SD 129), and terminal half-life was 5.1 days (SD 2.4).

Weekly repeated infusions of A1-PI at a dose of 60 mg/kg lead to serum A1-PI levels above the historical target threshold of 11 m M.


Clinical studies were conducted with Zemaira (alpha-proteinase inhibitor (human)) in 89 subjects (59 males and 30 females). The subjects ranged in age from 29 to 68 years (median age 49 years). Ninety-seven percent of the treated subjects had the PiZZ phenotype of A1-PI deficiency, and 3% had the MMALTON phenotype. At screening, serum A1-PI levels were between 3.2 and 10.1 M (mean of 5.6 m M). The objectives of the clinical studies were to demonstrate that Zemaira (alpha-proteinase inhibitor (human)) augments and maintains serum levels of A1-PI above 11 m M and increases A1-PI levels in ELF of the lower lung. In a double-blind, controlled clinical study to evaluate the safety and efficacy of Zemaira (alpha-proteinase inhibitor (human)) , 44 subjects were randomized to receive 60 mg/kg of either Zemaira (alpha-proteinase inhibitor (human)) or Prolastin® once weekly for 10 weeks. After 10 weeks, all subjects received Zemaira (alpha-proteinase inhibitor (human)) for an additional 14 weeks. All subjects were followed for a total of 24 weeks to complete the safety evaluation. The mean trough serum A1-PI levels at steady state (Weeks 7-11) in the Zemaira™ (alpha-proteinase inhibitor (human)) -treated subjects were statistically equivalent to those in the Prolastin®-treated subjects. Both groups were maintained above

11 m M (80 mg/dL). The mean (range and standard deviation) of the steady state trough serum antigenic A1-PI level for Zemaira (alpha-proteinase inhibitor (human)) -treated subjects was 17.7 m M (range 13.9 to 23.2, SD 2.5) and for Prolastin®-treated subjects was 19.1 m M (range 14.7 to 23.1, SD 2.2). The difference between the Zemaira (alpha-proteinase inhibitor (human)) and the Prolastin® groups was not considered clinically significant and may be related to the higher specific activity of Zemaira (alpha-proteinase inhibitor (human)) .

In a subgroup of subjects enrolled in the study (10 Zemaira (alpha-proteinase inhibitor (human)) -treated subjects and 5 Prolastin®-treated subjects), bronchoalveolar lavage was performed at baseline and at Week 11. Four A1-PI related analytes in ELF were measured: antigenic A1-PI, A1-PI:NE complexes, free NE, and functional A1-PI (anti-neutrophil elastase capacity, ANEC). A blinded retrospective analysis, which revised the prospectively established acceptance criteria showed that within each treatment group, ELF levels of antigenic A1-PI and A1-PI:NE complexes increased from baseline to Week 11. Free elastase was immeasurably low in all samples. The post-treatment ANEC values in ELF were not significantly different between the Zemaira (alpha-proteinase inhibitor (human)) -treated and Prolastin®-treated subjects (mean 1725 nM vs. 1418 nM).

No conclusions can be drawn about changes of ANEC values in ELF during the study period as baseline values in the Alpha1-Proteinase Inhibitor (Human), Zemaira™ (alpha-proteinase inhibitor (human)) -treated subjects were unexpectedly high. No A1-PI analytes showed any clinically significant differences between the Zemaira (alpha-proteinase inhibitor (human)) and Prolastin® treatment groups.

Table 2: ELF Analytes - change from baseline



Mean change from baseline

90% CI

A1-PI (nM)



822.6 to 1894.0



460.0 to 1439.7




-2032.3 to 856.1



-392.3 to 1387.2

A1-PI:NE Complexes (nM)



39.9 to 196.1



49.8 to 524.5

Subjects were also monitored for the presence of antibodies to HIV and markers for viral hepatitis (HAV, HBV, and HCV). Subjects who were negative for Hepatitis B surface antigen (HBsAg) at screening were vaccinated against Hepatitis B. Zemaira (alpha-proteinase inhibitor (human)) -treated subjects were tested six months after the end of treatment for HAV, HBV, HCV, HIV, and Parvovirus B19, and no evidence of viral transmission was observed. No subjects developed detectable antibodies to Zemaira (alpha-proteinase inhibitor (human)) .

Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.

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