ANTITRYPSIN AEROSOLIZED FOR CONGENITAL EMPHYSEMA

ANTITRYPSIN AEROSOLIZED FOR CONGENITAL EMPHYSEMA has proven effective in raising patients' anti-elastase levels in the lung, National Institutes of Health Pulmonary Branch chief Ronald Crystal, MD, reported May 4 at a drug development seminar in Washington, D.C. The recombinant DNA version of alpha 1 antitrypsin, under development by Cooper Labs, lacks the carbohydrate molecules found in the human plasma-derived product (Cutter Labs' Prolastin), he noted. As a result, half-life of the recombinant antitrypsin is reduced from several days to several hours, "and a third of it comes out in the urine," making it unfeasible for parenteral administration. To offset the stability problem, NIH researchers decided to experiment with aerosolized delivery despite the difficulty of reaching the lower respiratory tract, Crystal said. "We evaluated all the nebulizers that are commercially available," before selecting one for testing, he added. The drug was studied in several patients with hereditary antitrypsin deficiency with a single 200 mg dose, he reported. The dose was "far less than what we're dealing with" via I.V. administration. Subsequent measurements of antitrypsin levels in the epithelial lining fluid demonstrated that "over a period of 24 hours [the levels] continue to go above the normal range then go back down but remain functional," Crystal explained. The aerosolized delivery of antitrypsin also was demonstrated to be safe, the NIH researcher maintained. Patients were administered the plasma-derived version over a one-week period "until we've given considerably over a gram of the protein . . . with no problems at all," he said. Recombinant antitrypsin may eventually prove promising in the larger population of cigarette-induced emphysemics, Crystal declared. The direction of current research suggests that emphysema "is essentially a treatable disease," he asserted, predicting that data will eventually be sufficient to merit use of recombinant antitrypsin in treating cigarette-induced disease. Both the plasma-derived and rDNA antitrypsin products currently have methionine as the active site in their interaction with neutrophil elastase, which destroys lung tissue, Crystal explained. The "Achilles Heel" is that methionine "is very sensitive to oxidants" in cigarette smoke, he pointed out, adding that exposure to oxidants "renders antitrypsin impotent" as a lung protectant. "One of the real advantages of the recombinant molecule is that you can change the active site," Crystal noted. "The best one that has been found is a leucine at the active site." This produces a molecule which is "a terrific neutrophil elastase inhibitor, an excellent pepsin G inhibitor and is resistant to oxidation," he added. Crystal, who appeared at The NDA Pipeline Conference sponsored by "The Pink Sheet" and International Business Communications, spoke approvingly of Synergen and Ciba-Geigy's joint development project for leukoprotease inhibitor "which is the anti-elastase of the trachea and large bronchi." In preclinical trials in sheep "we're getting the levels certainly that you get from recombinant antitrypsin in humans and it remains functional," he explained. "So that's also a good candidate in terms of human therapy." The NIH researcher felt that safety questions may hold up development of Merck and ICI's separate work on anti-elastase compounds using "small molecular weight compounds." The chief theoretical advantage over the large molecules like antitrypsin, he explained, is that small weight inhibitors can "get inside that neutrophil." On the other hand, the smaller inhibitors also may pose a "risk because they can also cause physiologic kinds of actions in elastase that neutrophils have which may cause problems. So safety testing these may turn out to be at least . . . a longer evaluation." He noted that another problem, "the interaction of elastase and antitrypsin," is "essentially irreversible." "Most of the small molecular weight inhibitors -- not all of them -- being developed are not totally irreversible which means you have to get more in to provide the same physiological effect in terms of inhibiting the burden of elastase."