Alpha-1 Antitrypsin

Alpha-1 antitrypsin is an enzyme that can be used to treat protease-antiprotease imbalance in the lung. For patients with alpha-1 antitrypsin deficiency, this is a serious issue since because of the low levels of antiproteases in the lung, proteases predominant and lead to lung inflammation, tissue destruction, and a predisposition to emphysema. Currently, there are three FDA-approved alpha-1 antitrypsins for IV administration: Prolastin (Grifols), Zemaira (Aventis-Behring), and Aralast (Alpha Therapeutic Corp.). All of these products are derived by purification from human serum.

Inhaled alpha-1 antitrypsin has been studied as a potential therapy with generally encouraging results [26]. Siekmeier [27] summarized that “the data demonstrate the feasibility of alpha-1 antitrypsin inhalation for restoration of the impaired protease antiprotease balance, attenuation of the inflammation and neutralization of the excess activity of neutrophil elastase.” Inhaled alpha-1 antitrypsin may well be useful to COPD and CF as well as pure alpha-1 antitrypsin deficiency since protease-antiprotease imbalances have been suggested to contribute to both these respiratory diseases. Siekmeier [27] also noted that potentially the inhalation route may provide cheaper therapy than that for IV administration since only about 2% is delivered to the lung following IV delivery as compared to possibly 20%-30% that could be delivered to the lung following inhalation. The 20%-30% aerosol deposition value can only be achieved with optimized devices and formulations. Kamada [28] is developing inhaled alpha-1 antitrypsin as potential therapy for AAT deficiency and announced results from their European phase 2/3 clinical study in September 2014. These failed to meet either the primary “time to the first moderate or severe exacerbation event” or secondary exacerbation endpoints with the intent to treat (ITT) population. However, there were clinically relevant changes in various lung function measurements in the ITT population, as well as in the Most Frequent Exacerbators population, of which some were statistically significant. Inhaled AAT was also safe and well tolerated in the patients. Based on the strength of the lung function changes, especially in the Most Frequent Exacerbators population, Kamada still plans to file for approval in Europe and the United States. The complete data set from the phase 2/3 clinical study was presented in May 2015 [28]. The benefit of inhaled AAT treatment is also being evaluated in other patient populations including cystic fibrosis [28].

One additional opportunity that could enhance inhaled alpha-1 antitrypsin usage would be the availability of a recombinant human protein to reduce immunogenicity potential, increase product reproducibility, and potentially reduce costs if an appropriate manufacturing process can be developed.

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