Alpha-1 Antitrypsin Deficiency (AATD)


Zemaira® (CSL Behring) is an alpha1-proteinase inhibitor approved for use in chronic augmentation therapy and maintenance therapy for adults with alpha-1 antitrypsin deficiency (AATD) who have clinical evidence of emphysema.1 Zemaira is indicated for increasing the antigenic and functional serum levels of alpha-1 antitrypsin protein (AAT). The initial approval in the US occurred in 2003.1,2 

Mechanism of Action and Usage

AATD is a rare inherited condition that increases the risk of development of chronic obstructive pulmonary disease (COPD), emphysema, liver disease, vasculitis, and skin conditions.2,3 AATD is caused by mutations in the SERPINA 1 gene, resulting in the production of low or nonexisting levels of AAT.3 

AAT is a circulating antiprotease of the lower respiratory tract and an acute phase protein. The main activity of AAT is to inhibit neutrophil elastase, a protein that shows harmful activity against pulmonary tissue.2 By inhibiting neutrophil elastase, AAT protects tissues that contain elastin, such as lung tissue.4 

In homeostatic conditions, AAT is synthesized in the liver and released into the bloodstream. In AATD, AAT is abnormally produced and is released from liver cells in deficient amounts, therefore decreasing circulating levels of the protein.3 AAT deficiency renders individuals susceptible to lung problems, such as emphysema.4 

Get detailed prescribing information on the Zemaira monograph page at MPR.

Tackling AATD and reducing the progression of lung disease may be performed with augmentation therapy. Purified pooled human plasma AAT can be infused into the patient’s body, aiming to increase AAT serum levels as well as AAT lung epithelial lining fluid (ELF) levels to adequate concentrations. This treatment can then prevent additional damage to the lung tissue.5 Augmentation therapy is well tolerated and safe.4 There are several purified AATs available and manufactured from pooled human plasma, including Zemaira.3,5 Zemaira is indicated to increase AAT levels above a theoretical protective threshold of 11 μM and provide protection to the lower respiratory tract by equilibrating the protease to antiprotease balance.1 

The recommended dose of Zemaira is 60 mg/kg body weight administered weekly. The drug is supplied as a single-use vial at approximately 1000 mg, 4000 mg, or 5000 mg of functionally active alpha1-proteinase inhibitor, and it must be reconstituted before intravenous administration. The most common adverse reactions to Zemaira, reported in about 5% of participants in prelicensure clinical studies, include headache, sinusitis, upper respiratory infection, bronchitis, asthenia, fever, injection site hemorrhage, rhinitis, sore throat, and vasodilation.1 

Zemaira may be contraindicated in patients that have known hypersensitivity to components used to manufacture Zemaira or that have a history of anaphylaxis or immunoglobulin A (IgA) deficiencies.1 As a product manufactured from human plasma, there is a low risk for transmission of infectious agents, such as blood-borne viruses and prions.2 To mitigate this risk, the manufacturing process of Zemaira includes 2 viral clearance steps in addition to a thorough screening of the donated plasma.1,2

Safety and Efficacy

The safety, tolerability, and efficacy of Zemaira were evaluated in a double-blind and controlled clinical trial with 44 participants.6 The aim of this multicenter study was to compare Zemaira to Prolastin®, another human-derived AAT product that was available at the time of the study. The enrolled participants were randomized to receive 60 mg/kg of Zemaira or Prolastin each week for 10 weeks. After 10 weeks, all participants were infused with Zemaira for 14 weeks. The results of the study revealed that Zemaira was well tolerated, safe, and bioequivalent to Prolastin. Both Zemaira- and Prolastin-treated participants maintained AAT levels above the 11-μM threshold. No viral transmission was observed after Zemaira administration. The study also showed that ELF levels of antigenic AAT and AAT:neutrophil elastase complexes increased from baseline to week 11. 

A multicenter, randomized, double-blind, parallel-group, placebo-controlled trial, RAPID (NTC00261833), was performed postlicensure of Zemaira and enrolled 180 participants. This study compared Zemaira therapy to a placebo; 93 participants were infused with a 60 mg/kg dose of Zemaira and 87 participants were infused with a placebo for 24 months.7 The trial revealed that the decline in lung density was diminished in patients treated with Zemaira. However, no differences between the drug and placebo were observed for the treatment of exacerbations. Following the RAPID trial, an open-label extension study recruited 140 participants who were enrolled in the previous trial (NTC00670007). These participants received open-label Zemaira for 24 months. Participants from the Zemaira-treated group in the RAPID trial continued to experience benefits in the decline of the lung density. Participants who were in the placebo group in the RAPID trial and further moved to augmentation therapy in the extension trial experienced a decrease in the rate of lung density decline. This reduction was similar to the Zemaira-treated group. The study highlighted the ability of the augmentation therapy in slowing down emphysema progression and the possibility of considering this therapy for preserving the lung parenchyma of patients who show clinical evidence of emphysema resulting from severe AATD.7

References

1. Zemaira. Package insert. CSL Behring;  2019. Accessed August 19, 2021.

2. Kee S, Weber D, Popp B, et al. Pathogen safety and characterisation of a highly purified human alpha1-proteinase inhibitor preparation. Biologicals. 2017;47:25-32. doi:10.1016/j.biologicals.2017.03.003

3.Alpha-1 antitrypsin deficiency. National Organization for Rare Disorders. Accessed August 19, 2021.

4. Boerema DJ, An B, Gandhi RP, et al. Biochemical comparison of four commercially available human α1-proteinase inhibitors for treatment of α1-antitrypsin deficiency. Biologicals. 2017;50:63-72. doi:10.1016/j.biologicals.2017.08.010

5. Stoller JK, Aboussouan LS. A review of α1-antitrypsin deficiency. Am J Respir Crit Care Med. 2012;185(3):246-259. doi:10.1164/rccm.201108-1428CI

6.Stocks JM, Brantly M, Pollock D, et al. Multi-center study: the biochemical efficacy, safety and tolerability of a new alpha1-proteinase inhibitor, Zemaira. COPD. 2006;3(1):17-23. doi:10.1080/15412550500493220

7. Chapman KR, Burdon JGW, Piitulainen E, et al.; RAPID Trial Study Group. Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;386(9991):360-368. doi:10.1016/S0140-6736(15)60860-1

Reviewed by Debjyoti Talukdar, MD, on 8/23/2021.