Regulatory Decision Summary for ZEMAIRA

Congenital Alpha1-Antitrypsin Deficiency (AATD) is an autosomal co-dominant condition characterized by a reduction in serum AAT levels and an increased risk of emphysema and, to a lesser extent, liver disease. Among AAT deficient patients with emphysema, a significant minority also have a reversible component to their airways obstruction indicative of a hypersensitivity or asthmatic component. Smokers with severe AAT deficiency may develop emphysema by the 3^rd to 4^th decade, whereas non-smokers may develop emphysema in the 5^th to 6^th decades.

In addition to intravenous augmentation therapy with exogenous A1-PI, the management of patients with established airflow obstruction includes strong advice to avoid smoking, the use of inhaled bronchodilators, influenza and pneumococcal vaccination, supplemental oxygen when indicated, pulmonary rehabilitation for individuals with functional impairment, management of acute exacerbations of COPD including, as needed, brief courses of systemic corticosteroids, early antibiotic therapy for purulent exacerbations, and ventilatory support as needed. Selected individuals with severe functional impairment and airflow obstruction are considered for lung transplantation.

Based on the information provided in the submission, the results of the pivotal clinical study suggest that 60 mg/kg weekly IV infusions of Zemaira restore serum and alveolar alpha1-antitrypsin concentrations to protective levels. Although a higher dosing regimen (120 mg/kg) has been used, the duration of the exposure was relatively short (4 weeks only). As part of a commitment to the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA), CSL Behring plans on conducting a clinical trial using the 120 mg/kg dose.

When approved, Zemaira will offer another treatment option for patients with congenital alpha-1 antitrypsin deficiency emphysema.

The risks of treatment with Zemaira are hypersensitivity and allergic reactions. Due to these risks, Zemaira is contraindicated in immunoglobulin A (IgA)-deficient patients with antibodies against IgA.

To conclude, the effect of Zemaira treatment on reducing the neutrophil elastase burden in adults with documented severe alpha1-proteinase inhibitor deficiency is considered to outweigh the few safety issues identified. The benefit risk balance is therefore considered to be positive.