Zemaira (Alpha 1-Antitrypsin) - Clinical Pharmacology

CLINICAL PHARMACOLOGY

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-PI deficiency 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 µM, 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 µM 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™ 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™, 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 A₁-PI at a dose of 60 mg/kg lead to serum A₁-PI levels above the historical target threshold of 11 µM.

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 A₁-PI deficiency, and 3% had the M_MALTON phenotype. At screening, serum A₁-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 A₁-PI above 11 µM 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™, 44 subjects were randomized to receive 60 mg/kg of either Zemaira™ or Prolastin® (a commercially available Alpha₁-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 A₁-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 A₁-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 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™-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 A₁-PI analytes showed any clinically significant differences between the Zemaira™ and Prolastin® treatment groups.

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™.