Alpha-1 Antitrypsin Deficiency (AATD)


History of Drug Development and Food and Drug Administration Approval

Glassia® is an alpha1-proteinase inhibitor used for chronic augmentation and maintenance therapy in adults with emphysema due to severe alpha-1 antitrypsin deficiency (AATD). Kamada Ltd., the Israeli company that developed Glassia, submitted a biologics license application to the US Food and Drug Administration (FDA) on June 2, 2009, seeking approval for the first liquid, injectable intravenous treatment for AATD. The application was accepted by the FDA for review on August 4, 2009. On July 6, 2010, the FDA approved Glassia as a novel intravenous treatment for AATD.1

Mechanism of Action and Pharmacokinetics 

AATD results from mutations in the SERPINA1 gene and is inherited in a codominant pattern from both parents. The congenital genetic mutations result in little or no functional alpha-1 antitrypsin protein (AAT) being produced in the liver cells. When small amounts of AAT are produced, these proteins are dysfunctional and are not released from the liver cells into the bloodstream in a normal manner, causing liver damage due to accumulation within the cells. Low levels of circulating AAT confirm a diagnosis of AATD.2 

These low or non-existent levels of serum AAT do not provide effective inhibition of neutrophil elastase in the lungs, allowing this protease enzyme to destroy normal alveolar lung tissue. This later manifests in the progression of lung diseases such as emphysema or chronic obstructive pulmonary disease (COPD).2

Glassia increases the antigenic and functional serum concentrations of AAT to improve anti-neutrophil elastase capabilities in the epithelial lung tissues.3 Glassia is the first liquid preparation of purified human AAT, whereas the previous 3 therapies for AATD are in powder form and require advanced preparation before intravenous administration.4 Kamada plans to release a breakthrough inhaler version of Glassia in the future, such that the AAT treatment can immediately be absorbed into the lung tissues.4 

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

Preparation

The Glassia phosphate-buffered saline solution contains 2% active AAT that is prepared from human plasma obtained from US-licensed plasma collection centers using a modified version of the cold ethanol fractionation process.3 The AAT is purified using chromatographic methods and evaluated rigorously to remove contamination with viruses like human immunodeficiency virus (HIV) or hepatitis. Two methods are used to remove or inactivate such viruses if present, including nanofiltration and solvent/detergent treatment using a mixture of tri-(n-butyl) phosphate and polysorbate 80.3

Safety and Efficacy

The most serious adverse event during clinical trials of Glassia was the exacerbation of COPD, while the most common side effects included headache and upper respiratory infections in >0.5% of infusions. Researchers analyzed the safety profile of Glassia in a randomized, double-blind, active-control trial and in an open-label, non-parallel, dose-escalation trial. In the active-control trial, 33 patients with AATD received weekly infusions of Glassia and 17 patients in the control group received Prolastin® (another alpha1-proteinase inhibitor) for 12 weeks; all 50 patients then received Glassia only for another 12 weeks in a cross-over trial. In the dose-escalation trial, 18 patients received a single infusion of Glassia at 30, 60, or 120 mg/kg doses. In both trials, adverse events included cough, upper respiratory tract infection, headache, sinusitis, chest discomfort, and hepatic enzyme elevations.3

Investigators analyzed possible immunogenicity to Glassia during a randomized controlled trial, and only 1 individual developed low levels of anti-Glassia antibodies that disappeared by the end of the study despite repeated exposure to Glassia. No adverse immune system responses were observed.3

These studies concluded that Glassia was as efficacious as Prolastin, was well-tolerated by patients, and maintained a similar safety profile to Prolastin.5 In the cross-over clinical trial, 100% of the 50 patients treated with Glassia obtained antigenic AAT levels greater than 11 µM during weeks 7 to 12 of their treatment. Of the original 33 patients prior to the cross-over, 66.7% maintained functional AAT levels above the 11 µM threshold, while the other 33.3% did not.6 

Contraindications to taking Glassia include a patient history of anaphylaxis or severe systemic responses to AAT products as well as immunoglobulin A (IgA)-deficient patients with antibodies against IgA. Due to the possibility of Glassia products containing trace IgA amounts, patients should be monitored throughout infusions for any signs of hypersensitivity, and epinephrine should be at hand in case of any anaphylactic reactions.6 

Glassia is for intravenous administration only, with a recommended dosage of 60 mg/kg body weight once weekly. Glassia is available as a single-use vial containing 1 g of functional AAT in 50 mL of ready-to-use buffer solution. Storage instructions state that Glassia should not be frozen, rather, it should be stored at 2 to 8 °C or 36 to 46 °F. Once removed from refrigeration, Glassia should be used within 1 month.3 

Infusions may be performed in a physician’s office, an infusion center, or at home via a home health agency; with proper training it may also be administered by the patient themselves or a caregiver. Infusion time typically takes approximately 15 minutes based on a maximum rate of 0.2 mL/kg/min at the recommended dosage of 60 mg/kg.6

References

  1. Glassia FDA approval history. Drugs.com. Accessed August 12, 2021.
  2. Alpha-1 antitrypsin deficiency. MedlinePlus. Updated August 18, 2020. Accessed August 12, 2021.
  3. Glassia. RxList. Updated April 11, 2018. Accessed August 12, 2021.
  4. Cohen T. Kamada gets US FDA approval for AATD drug Glassia. Reuters. July 2, 2010. Accessed August 12, 2021.
  5. Sandhaus RA, Stocks J, Rouhani FN, Brantly M, Strauss P. Biochemical efficacy and safety of a new, ready-to-use, liquid alpha-1-proteinase inhibitor, Glassia (alpha1-proteinase inhibitor (human), intravenous). COPD. 2014;11(1):17-25. doi:10.3109/15412555.2013.804500
  6. Glassia: the first FDA-approved liquid alpha1 augmentation therapy. Accessed August 12, 2021.

Reviewed by Harshi Dhingra, MD, on 8/16/2021.

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