A novel anti-infective approach is to exploit stresses already imposed on invading organisms in vivo. Iron (Fe) metabolism is a key vulnerability of infecting bacteria because organisms require iron for growth. The applicant proposed that a strategy using the metal gallium (Ga) to disrupt bacterial iron metabolism holds promise as an antimicrobial approach. Due to its chemical similarity to iron, the applicants state that gallium can substitute for iron in many biologic systems and inhibit iron-dependent processes. The applicant has complied data to show that gallium kills the opportunistic pathogen Pseudomonas aeruginosa (including antibiotic resistant strains), is active against biofilms, and treats 3 different models of Pseudomonas aeruginosa infections. These data, the fact that gallium nitrate (trade name, Ganite) is FDA approved for intravenous (IV) administration, and the dearth of new antibiotics in development indicate to the applicant that gallium could be a promising new therapeutic for Pseudomonas aeruginosa infections. An initial Phase 1b study in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa indicated to the applicant that IV gallium appeared to be safe, well tolerated, has a good pharmacokinetic profile, and is associated with a clinically meaningful improvement in lung function 14 days and 28 days after the start of a 5 day infusion of IV gallium. The applicant proposes a proof of concept Phase 2 clinical trial to confirm the prior findings of efficacy and provide further data regarding the safety and pharmacokinetics of IV gallium in cystic fibrosis subjects infected with Pseudomonas aeruginosa.
The Specific Aims of the study are to: 1) assess the pulmonary function response rate at day 28 in cystic fibrosis patients receiving a 5-day continuous IV gallium and placebo; and 2) to assess the safety and pharmacokinetics of a 5 day continuous IV infusions of gallium in adult cystic fibrosis subjects compared to placebo.
Our data shows that gallium (Ga) kills the opportunistic pathogen Pseudomonas aeruginosa (including antibiotic resistant strains), is active against biofilms, and treats 3 different model P. aeruginosa infections. We have also shown that Ga is safe and well tolerated in our phase 1b study in cystic fibrosis (CF) with preliminary evidence of clinical efficacy. We propose to assess efficacy of Ga in a proof of concept randomized controlled trial in this patient population which if successful, could provide a novel agent to fight chronic infections with P. aeruginosa in other disease settings beyond CF.
| West, Natalie E; Goss, Christopher H; Nichols, David P (2018) The Long and the Short of It in Cystic Fibrosis Clinical Research Outcomes. Ann Am Thorac Soc 15:430-431 |
| Goss, Christopher H; Sykes, Jenna; Stanojevic, Sanja et al. (2018) Comparison of Nutrition and Lung Function Outcomes in Patients with Cystic Fibrosis Living in Canada and the United States. Am J Respir Crit Care Med 197:768-775 |
| Ramos, Kathleen J; Somayaji, Ranjani; Nichols, David P et al. (2018) Comparative Effectiveness Research in Pediatric Respiratory Disease: Promise and Pitfalls. Paediatr Drugs 20:1-7 |
| Lechtzin, Noah; Mayer-Hamblett, Nicole; West, Natalie E et al. (2017) Home Monitoring of Patients with Cystic Fibrosis to Identify and Treat Acute Pulmonary Exacerbations. eICE Study Results. Am J Respir Crit Care Med 196:1144-1151 |
| Sack, Cora S; Goss, Christopher H (2017) Yet Again, Air Pollution Impacts Lung Health. Ann Am Thorac Soc 14:1761-1762 |
| Stephenson, Anne L; Sykes, Jenna; Stanojevic, Sanja et al. (2017) Survival Comparison of Patients With Cystic Fibrosis in Canada and the United States: A Population-Based Cohort Study. Ann Intern Med 166:537-546 |
| Muhlebach, Marianne Sponer; Beckett, Valeria; Popowitch, Elena et al. (2017) Microbiological efficacy of early MRSA treatment in cystic fibrosis in a randomised controlled trial. Thorax 72:318-326 |
| Heltshe, Sonya L; Cogen, Jonathan; Ramos, Kathleen J et al. (2017) Cystic Fibrosis: The Dawn of a New Therapeutic Era. Am J Respir Crit Care Med 195:979-984 |
| Ramos, Kathleen J; Quon, Bradley S; Heltshe, Sonya L et al. (2017) Heterogeneity in Survival in Adult Patients With Cystic Fibrosis With FEV1 < 30% of Predicted in the United States. Chest 151:1320-1328 |
| Ramos, Kathleen J; Sack, Coralynn S; Mitchell, Kristina H et al. (2017) Cystic Fibrosis is Associated with Adverse Neonatal Outcomes in Washington State, 1996-2013. J Pediatr 180:206-211.e1 |
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