The purpose of this research is to determine the efficacy of orally administered recombinant human lactoferrin (rhLF) in Phase II clinical trials in patients with mild to moderate asthma. Asthma is one of the most prevalent chronic inflammatory diseases in the United States affecting approximately 15 percent of the population. Despite intensive research on asthma over the past decade the prevalence, morbidity and mortality rates continue to increase in the U.S. and the developed world and there remains a large unmet medical need for new orally administered drugs that can more effectively and safely treat this disease. Lactoferrin is a multifunctional immunomodulatory protein found in serum and exocrine secretions such as milk and colostrum where it acts as a component of the primary host defense system. It is also a component of the neutrophil secondary granules and is released locally at the site of inflammation. RhLF, a recombinant version of the protein, is identical to the native protein in all material respects, differing only in the nature of its glycosylation. Pharmaceutical grade rhLF can be produced at large scale (tons of product per year). We have shown that oral rhLF protects against airway effects and inflammatory infiltration in both sheep and primate models of asthma. In the sheep model of allergic asthma, oral rhLF inhibited the early and late asthmatic responses and airway hypersensitivity by up to 77 percent, 90 percent and 100 percent, respectively. These results are comparable or superior to those obtained by leading approved drugs such as ZileutonTM and Montelukast Sodium (Singulair(tm)) in the same preclinical model. In Phase I of this SBIR grant, the anti-asthma activity of rhLF, previously observed in sheep, was confirmed in Cynmolgus monkeys, a non-human primate model of asthma. The primate work also helped identify an appropriate clinical dose for our Phase 2 trial. Details of this work are provided in the Phase I Report accompanying this application. RhLF's anti-asthma activity appears to act by a novel mechanism. Oral rhLF induces the production on key cytokines, including IL-18, in the gut resulting in a systemic TH2 to TH1 shift that helps reduce the inflammation associated with asthma. Oral rhLF has also shown to be safe and well tolerated in animal studies and in human trials. RhLF has been administered to mice and monkeys at doses as high as 1000 mg/kg and for up to 183 days in a 6-month monkey safety-toxicity study. No drug related adverse events were noted during the treatment phase, in laboratory tests or on histopathology. In humans, rhLF has been administered at a dose of up to 15 g in a 24 hour period and for up to 9 g/day for sustained periods of time. Oral rhLF has been administered orally to 211 people without a single drug related serious adverse event. Few orally administered effective anti-asthma drugs are available to patients. Given the robust safety profile and ease of administration of oral rhLF there exists a possibility that rhLF may represent an exciting, safe and novel therapy for asthma. Thus, we are requesting support to conduct a Phase 2 human clinical trial to evaluate the efficacy of oral rhLF in asthmatic patients. This research will seek to determine the efficacy of oral lactoferrin in treating the symptoms of mild to moderate asthma. We will conduct a 28 day double-blind, placebo-controlled clinical trial in 30 patients with mild to moderate asthma to assess the effectiveness of lactoferrin in relieving asthma symptoms as measured by standard parameters including FEV, asthma symptom scores and use of inhaled beta2-agonist rescue medications. Patient enrollment and evaluation will be conducted independently at major academic institutions by independent clinicians
