Alpha-1 antitrypsin replacement therapy for the genetic disorder alpha-1 antitrypsin deficiency has no proven clinical benefit, according to a systematic review by researchers at the Nordic Cochrane Center at Rigshospitalet in Copenhagen, Denmark. The review concludes that considering the lack of evidence for its benefits, and possible adverse effects, the expensive treatment should not be recommended.

Alpha-1 antitrypsin deficiency affects fewer than one in 1,600 people, causing chronic lung disease. Those who inherit the disorder have low levels of the protein alpha-1 antitrypsin, also called alpha-1 proteinase inhibitor, which protects the tissue of the lungs from destruction by the body’s own white blood cells. At a relatively young age, sufferers can experience symptoms of emphysema, including shortness of breath and wheezing.

The aim of the alpha-1 antitrypsin replacement therapy is to give the patient back the protective protein they are missing—potentially limiting damage to the lungs and, ultimately, preventing early death. The protein is extracted from blood donated by health volunteers.

The researchers reviewed data from two trials involving a total of 140 people with the disorder, all of whom were at a high genetic risk of developing chronic lung disease. In one trial, patients were given intravenous alpha-1 antitrypsin or a placebo every 4 weeks for 3 years. In the other trail, the protein or placebo was given weekly for a minimum of 2 years. Researchers found that there was no difference between treatment and control groups in terms of exacerbations of lung disease or quality of life.

Combining the results from the trials, the review found no evidence of a clinical important effect on lung function; indeed the results suggested modest harm, or at best no effect. In contrast, the treatment might cause a reduction in the deterioration of lung appearance on CT scan, but it is not clear whether this is a clinically meaningful difference.

Based on this evidence, the researchers say the treatment, which costs up to $150,000 a year in the United States, cannot be recommended.

“The drug has not shown any clinical benefit, is extremely costly and has important adverse effects,” said Peter Gøtzsche, lead researcher from the Cochrane Center. “In view of the lack of evidence and high cost of treatment, treating alpha-1 antitrypsin deficiency by replacement therapy cannot be recommended.”

The researchers say recommendations by the American Thoracic Society and European Respiratory Society that promote alpha-1 antitrypsin replacement are misguided.

“Both societies recommend augmentation therapy for patients with breathing problems related to alpha-1 antitrypsin deficiency. In our opinion, these recommendations are not reasonable,” said Gøtzsche.

Neither of the trials included in the review reported mortality data and the researchers point out that adverse events are not well reported. In previous studies, a small proportion of patients suffered allergic reactions and breathing difficulties following treatment.