Zemaira .ALPHA.1-PROTEINASE Inhibitor Human Kit — NDC 0053-7202-02 (Billing 00053-7202-02)

CLINICAL PHARMACOLOGY Alpha 1 -proteinase inhibitor (A 1 -PI) deficiency is a chronic, hereditary, autosomal, co-dominant disorder that is usually fatal in its severe form. Low blood levels of A 1 -PI (i.e., below 11 µM) are most commonly associated with progressive, severe emphysema that becomes clinically apparent by the third to fourth decade of life. In addition, PiSZ individuals, whose serum A 1 -PI levels range from approximately 9 to 23 µM are considered to have moderately increased risk for developing emphysema, regardless of whether their serum A 1 -PI levels are above or below 11 µM.

1 Not all individuals with severe genetic variants of A 1 -PI deficiency have emphysema. Augmentation therapy with Alpha 1 -Proteinase Inhibitor (Human) is indicated only in patients with severe congenital A 1 -PI deficiency who have clinically evident emphysema. A recent registry study showed 54% of A 1 -PI deficient subjects had emphysema.

2 Another registry study showed 72% of A 1 -PI deficient subjects had pulmonary symptoms. 3 Smoking is an important risk factor for the development of emphysema in patients with A 1 -PI deficiency. Approximately 100 genetic variants of A 1 -PI deficiency can be identified electrophoretically, only some of which are associated with the clinical disease.

4,5 Ninety-five percent of A 1 -PI deficient individuals are of the severe PiZZ phenotype. Up to 39% of A 1 -PI deficient patients may have an asthmatic component to their lung disease, as evidenced by symptoms and/or bronchial hyperreactivity. 2 Pulmonary infections, including pneumonia and acute bronchitis, are common in A 1 -PI deficient patients and contribute significantly to the morbidity of the disease.

Augmenting the levels of functional protease inhibitor by intravenous infusion is an approach to therapy for patients with A 1 -PI deficiency. However, the efficacy of augmentation therapy in affecting the progression of emphysema has not been demonstrated in randomized, controlled clinical trials. The intended theoretical goal is to provide protection to the lower respiratory tract by correcting the imbalance between neutrophil elastase and protease inhibitors.

Whether augmentation therapy with Zemaira ® or any A 1 -PI product actually protects the lower respiratory tract from progressive emphysematous changes has not been evaluated. Individuals with endogenous levels of A 1 -PI below 11 µM, in general, manifest a significantly increased risk for development of emphysema above the general population background risk. 5,6,7,8 Although the maintenance of blood serum levels of A 1 -PI (antigenically measured) above 11 µM has been historically postulated to provide therapeutically relevant anti-neutrophil elastase protection 9 , this has not been proven.

Individuals with severe A 1 -PI deficiency have been shown to have increased neutrophil and neutrophil elastase concentrations in lung epithelial lining fluid compared to normal PiMM individuals, and some PiSZ individuals with A 1 -PI above 11 µM have emphysema attributed to A 1 -PI deficiency. 1 These observations underscore the uncertainty regarding the appropriate therapeutic target serum level of A 1 -PI during augmentation therapy. Mechanism of Action Pulmonary disease, particularly emphysema, is the most frequent manifestation of A 1 -PI deficiency.

5 The pathogenesis of emphysema is understood to evolve as described in the "protease-antiprotease imbalance" model. A 1 -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 A 1 -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 A 1… [Excerpted — this section continues on DailyMed.]

Mechanism of Action Pulmonary disease, particularly emphysema, is the most frequent manifestation of A 1 -PI deficiency. 5 The pathogenesis of emphysema is understood to evolve as described in the "protease-antiprotease imbalance" model. A 1 -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 A 1 -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 A 1 -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 ® serves as A 1 -PI augmentation therapy in this patient population, acting to increase and maintain serum levels and lung epithelial lining fluid (ELF) levels of A 1 -PI. In 18 subjects treated with a single dose (60 mg/kg) of Zemaira ® , the mean area under the curve (AUC) and standard deviation (SD) were 144 µM × day (SD 27), maximum serum concentration was 44.1 µM (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 A 1 -PI at a dose of 60 mg/kg lead to serum A 1 -PI levels above the historical target threshold of 11 µM.

The clinical benefit of the increased blood levels of A 1 -PI at the recommended dose for any A 1 -PI product has not been established.

CLINICAL STUDIES Clinical studies were conducted with Zemaira ® 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 A 1 -PI deficiency, and 3% had the M MALTON phenotype.

At screening, serum A 1 -PI levels were between 3.2 and 10.1 µM (mean of 5.6 µM). The objectives of the clinical studies were to demonstrate that Zemaira ® augments and maintains serum levels of A 1 -PI above 11 µM and increases A 1 -PI levels in ELF of the lower lung. In a double-blind, controlled clinical study to evaluate the safety and efficacy of Zemaira ® , 44 subjects were randomized to receive 60 mg/kg of either Zemaira ® or Prolastin ® (a commercially available Alpha 1 -Proteinase Inhibitor [Human] product) once weekly for 10 weeks.

After 10 weeks, all subjects received Zemaira ® for an additional 14 weeks. All subjects were followed for a total of 24 weeks to complete the safety evaluation. The mean trough serum A 1 -PI levels at steady state (Weeks 7-11) in the Zemaira ® -treated subjects were statistically equivalent to those in the Prolastin ® -treated subjects.

Both groups were maintained above 11 µM (80 mg/dL). The mean (range and standard deviation) of the steady state trough serum antigenic A 1 -PI level for Zemaira ® -treated subjects was 17.7 µM (range 13.9 to 23.2, SD 2.5) and for Prolastin ® -treated subjects was 19.1 µM (range 14.7 to 23.1, SD 2.2). The difference between the Zemaira ® and the Prolastin ® groups was not considered clinically significant and may be related to the higher specific activity of Zemaira ® .

In a subgroup of subjects enrolled in the study (10 Zemaira ® -treated subjects and 5 Prolastin ® -treated subjects), bronchoalveolar lavage was performed at baseline and at Week 11. Four A 1 -PI related analytes in ELF were measured: antigenic A 1 -PI, A 1 -PI:NE complexes, free NE, and functional A 1 -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 A 1 -PI and A 1 -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 ® -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 Zemaira ® -treated subjects were unexpectedly high. No A 1 -PI analytes showed any clinically significant differences between the Zemaira ® and Prolastin ® treatment groups. Table 2: ELF Analytes - change from baseline Analyte Treatment Mean change from baseline 90% CI A 1 -PI (nM) Zemaira ® 1358.3 822.6 to 1894.0 Prolastin ® 949.9 460.0 to 1439.7 ANEC (nM) Zemaira ® -588.1 -2032.3 to 856.1 Prolastin ® 497.5 -392.3 to 1387.2 A 1 -PI:NE Complexes (nM) Zemaira ® 118.0 39.9 to 196.1 Prolastin ® 287.1 49.8 to 524.5 The clinical efficacy of Zemaira ® or any A 1 -PI product in influencing the course of pulmonary emphysema or pulmonary exacerbations has not been demonstrated in adequately powered, randomized, controlled clinical trials.

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 ® -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 ® .