Alpha 1-antitrypsin deficiency future or investigational therapies
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
Overview
Alpha 1-antitrypsin deficiency (A1AD) is currently being investigated for the prevention of polymer formation in the liver.
Future or Investigational Therapies
Treatments currently being studied include recombinant and inhaled forms of A1AT. Other experimental therapies are aimed at the prevention of polymer formation in the liver.
Pitfalls of Therapy:
- Despite the isolation and cloning of the alpha-1 AT gene, the efficacy of augmentation therapy remains controversial due to the lack of large randomized trials that define the treatment regimens and target population. The current goal of therapy is to raise the level of alpha-1 AT in the plasma, and therefore the lung interstitium above the ‘protective’ threshold of 11 umol/L (80 mg/dl). There are basically two types of treatment for this disease, ‘augmentation’ therapy, and organ transplantation.
- Endogenous enhancement of alpha-1 AT production has been attempted pharmacologically with medications such as Danazol, Tamoxifen and estrogen/progesterone combinations based on the observation that alpha-1 AT levels increase as an acute phase reactant in times of stress (including pregnancy). Unfortunately, the alpha-1 AT levels do not increase enough to warrant therapy.
- Exogenous augmentation via aerosolization of either pooled human alpha-1 AT, or recombinant alpha-1 AT has been attempted, and both are thought to be safe and effective. Large clinical trials are currently underway.
- Gene therapy uses viruses that have been altered so they can not replicate to ‘infect’ and integrate their genome (with the cDNA of alpha-1 AT) into host cells with the goal of the host cell manufacturing endogenous alpha-1 AT. Unfortunately, in the initial studies, expression of the gene was limited, and the alpha-1 AT levels did not increase above the protective threshold.
- Exogenous augmentation via IV infusion of pooled human alpha-1 AT is the only approved method of augmentation therapy for patients with alpha-1 AT deficiency. Although being safe, well-tolerated, and without significant side effects, its clinical efficacy is still unproven. In addition, the goal plasma level is not known, especially since there is a cohort of patients with severe alpha-1 AT deficiency that are not symptomatic. Unfortunately, there has not been a randomized, double-blinded, placebo-controlled trial in patients with alpha-1 AT deficiency with and without symptoms.
- A recent observational study compared the rate of decline in FEV1 in 97 Danish ex-smokers to 198 German ex-smokers, both of whom had severe alpha-1 AT deficiency. The German subjects received weekly infusions of 60 mg/kg alpha-1 AT, and the Danish did not receive augmentation therapy. The Germans had a slower rate of decline in their FEV1 as compared with the Danes (-53 ml/yr vs. -75 ml/yr, p=0.002).
- Although weekly infusions are the only FDA approved regimen, monthly infusions (250 mg/kg) seem to have the same efficacy and safety and are widely used.
- The ATS recommends augmentation therapy for patients with alpha-1 AT phenotypes PI ZZ, PI Z null or PI null null with alpha-1 AT levels < 11 umol/L and airflow obstruction. Conversely, the Canadian Thoracic Society recommends waiting until the results of a large trial establish its efficacy. Additionally, although it is thought that severe COPD is associated with negligible benefit, a lower limit of FEV1 below which augmentation therapy should be withheld has not been proposed.
- It is crucial that these patients don’t smoke, and are treated with bronchodilators, just as other patients with airways obstruction. They should also receive pneumococcal and influenza vaccines.
- A years worth of IV augmentation therapy costs approximately $25,000 - $35,000 (90% of which is for the drug).
- There have not been any cases of HIV or hepatitis transmitted by pooled human alpha-1 AT.
- Transplantation of both lungs and liver has been offered to patients with end stage disease. Liver transplantation has the added benefit of correcting the underlying disorder, as the new liver will produce and secrete alpha-1 AT. There is no data to support the use of augmentation therapy after lung transplantation, although some authors suggest augmentation therapy during times of increased neutrophil burden in the lung.