GTC proposes a Fast-Track Phase 1/II program to develop recombinant human alpha-l-proteinase inhibitor (tg-A1PI) for cystic fibrosis inhalation therapy. Tg-A1PI will be made in potentially unlimited supply in a novel production system -- milk from transgenic goats. This represents a new therapeutic indication, manufacturing method, formulation and administration route for a plasma-derived protein already approved for intravenous treatment of genetic alpha-l-antitrypsin deficiency disease. Preliminary studies have established the feasibility of restoring lung function with aerosol A1PI. GTC has established transgenic goats that produce tg-A1PI in their milk at commercially attractive levels. GTC also has developed proprietary technologies for isolating and purifying recombinant transgenic proteins from goat milk. The Specific Aims of this Phase I proposal are: preformulation characterization of A1PI; formulation of tg-A1PI for aerosol delivery; and characterization of the A1PI transgene from transgenic founder goats to select the best production line for herd scale-up. This will lead to a Phase II project, detailed in the accompanying proposal, for preclinical testing in animals to establish safety, pharmacokinetics, and efficacy in an experimental animal model. Tg-A1PI inhalation therapy also may be useful for asthma, acute respiratory distress syndrome, and as an adjunct to gene therapy. PROPOSED COMMERCIAL APPLICATION: GTC proposes to develop an aerosol formulation of human recombinant tg- A1PI for CF therapy. This would fill immediate unmet needs for primary and adjunct therapy for CF and other hypersecretory pulmonary diseases, for improved administration route and efficacy (especially for children with CF), and for a biologically safe and potentially unlimited supply of therapeutic protein that currently is purified from plasma in limited amounts. The total projected clinical need is 2,500 for CF and 1,000 for AAT deficiency. The total market values for CF alone is estimated as $200M annually in the US
