Fixed Combination of Glycopyrrolate and Formoterol MDI (GFF MDI) Demonstrates Superior Inspiratory Capacity Compared to Tiotropium DPI in a Randomized, Double-Blind, Placebo-Controlled Phase 2b Study in Patients with Moderate to Very Severe COPD

Rationale: In patients with COPD, changes in inspiratory capacity (IC) have shown a higher correlation to patient-focused outcomes, such as dyspnea with exercise, than other standard spirometric measurements. Changes in IC reflect changes in hyperinflation (Celli, 2003). Tiotropium dry powder inhaler (DPI) is a once-daily inhaled anticholinergic, and previous studies have demonstrated improvements in IC following its administration. Pearl Therapeutics’ (Pearl) GFF MDI is an inhaled bronchodilator comprised of glycopyrrolate (GP), a long-acting muscarinic antagonist (LAMA) and formoterol fumarate (FF), an established, long-acting beta-2 agonist (LABA), delivered via an HFA 134a MDI. Pearl’s proprietary porous particle technology allows the formulation of FF, GP and the combination thereof in MDI format, with highly stable, robust and aerodynamically efficient drug delivery. As part of a large Phase IIb study evaluating the safety and efficacy of GFF MDI, Pearl evaluated improvements in IC following administration of GFF MDI compared to tiotropium DPI and placebo following chronic dosing. Methods: A randomized, double-blind, customized, unbalanced, incomplete block, crossover study was conducted in patients with moderate to very severe COPD (NCT01085045). This design ensured maximum power for key assessments. Two doses of GFF MDI (72/9.6 and 36/9.6 µg) were compared to tiotropium DPI 18 µg and placebo MDI. All actives and placebo were administered twice daily for 1 week, except tiotropium (open-label), which was administered once daily for 1 week. Changes in peak IC were assessed on Day 1 and on Day 7 relative to average pre-dose baseline at the start of treatment. Results: 118 patients were randomized into the study. Both doses of GFF MDI (72/9.6 and 36/9.6 µg) and tiotropium DPI were superior to placebo (412 mL, 328 mL and 263 mL respectively; p<0.0001 all comparisons) on Day 1, and on Day 7 (265 mL, 293 mL and 170 mL respectively; p<0.0004 all comparisons). GFF MDI 72/9.6 µg was superior to tiotropium DPI on Day 1 and Day 7 (149 mL and 95 mL improvement respectively: p<0.05 for both comparisons). GFF-MDI 36/9.6 µg demonstrated a numeric advantage compared to tiotropium DPI on Day 1 (65 mL) and was superior on Day 7 (124 mL, p<0.01). Conclusion: GFF MDI, a novel fixed dose LAMA/LABA combination bronchodilator, demonstrated superiority to placebo and statistically significant (GFF MDI 72/9.6 µg) and numerically greater (GFF MDI 36/9.6 µg) improvements in IC compared to tiotropium DPI. This supports the further development of GFF MDI in patients with COPD and, specifically, a formal evaluation of the effects of GFF MDI on exercise.