Safety and Efficacy of Proprietary Glycopyrronium MDI in COPD
Safety and Efficacy of Proprietary Glycopyrronium MDI in COPD
The current study assessed GP administered by an MDI using a proprietary lipid-based porous-particle. The FEV1 data obtained during this study indicate that a single-dose of GP MDI yields statistically significant, dose-dependent, and clinically relevant bronchodilation at all doses compared with Placebo MDI. In terms of peak improvement in FEV1, the efficacy of GP MDI 57.6 and 115.2 μg bracketed that of TIO 18 μg. Although both GP MDI 14.4 and 28.8 μg demonstrated clinically relevant and statistically significant peak improvement in FEV1 compared with Placebo MDI, the magnitude of these improvements was numerically lower than those observed with TIO 18 μg.
The primary efficacy results are corroborated by the secondary efficacy variables: 12- and 24-hour post-dose FEV1, FEV1 AUC0–12, FEV1 AUC0–24, and FEV1 AUC12–24, with statistically significant greater mean changes from test-day baseline compared with Placebo MDI for all comparisons, with the exception of GP MDI 28.8 μg for 24-hour post-dose FEV1. Point-estimates for the majority of FEV1 parameters for GP MDI 57.6 and 115.2 μg were within ± 50 mL compared with TIO. All GP MDI doses demonstrated a rapid onset of action, and the 115.2 μg dose demonstrated a significantly faster onset than TIO 18 μg. With regard to the duration of action of GP MDI, several observations confirm that GP MDI is appropriate for twice daily (BID) dosing. For all GP MDI doses, the changes from baseline in FEV1 compared to Placebo MDI at 12 hours post-dose were appreciably greater than the changes at 24 hour post-dose, while these values were more consistent for TIO compared to Placebo MDI. Similarly, FEV1 AUC0–12 was greater than FEV1 AUC12–24 for all GP doses compared with Placebo MDI, while for TIO the difference from Placebo MDI in FEV1 AUC maintained close to 1:1 ratio across the 0- to 12- and 12- to 24-hour intervals. All doses of GP MDI were safe and well tolerated. The most frequently reported AE was dry mouth, which was reported for a similar proportion of study patients following Placebo MDI, GP MDI, and TIO (0–14.3% of patients).
Placing the data from the current study into context with those of existing glycopyrronium formulations is warranted. A 14-day PK study of NVA237 (Seebri® Breezehaler®, Novartis Europharm Limited, Horsham, West Sussex, United Kingdom) in doses of 25, 40, 100, and 200 μg found that the median time to reach maximal plasma concentration (tmax) was similar between NVA237 (5–6.5 minutes post-inhalation), to the 6 minutes for GP MDI 28.8 to 115.2 μg observed in the current study. The mean terminal elimination half-life (t1/2) of NVA237 is reported to range between 13 and 22 hours compared with 6.3 to 9.6 hours for GP MDI 28.8 to 115.2 μg. It remains subject to debate whether these PK traits are generalizable to specific benefits in lung function which favor once-daily (QD) or BID dosing.
In comparing the efficacy of GP MDI observed in the current study with that of NVA 237 50 μg administered QD in the Glycopyrronium bromide in COPD airWays clinical Study 1 (GLOW1) trial; treatment with NVA237 resulted in an improvement in 24-hr post dose FEV1 (average of mean 23 hours 15 minutes, and 23 hours 45 minutes post-dose values) of 105 mL after initial dosing compared with placebo (P < .001). In the GLOW2 study, study patients received either NVA 237 50 μg, TIO 18 μg or placebo once-daily (QD), the differences from placebo in 24-hr post-dose FEV1 after initial dosing were 91 and 83 mL for NVA 237 and TIO, respectively. For the current study, GP MDI 115.2, 57.6, 28.8, and 14.4 μg resulted in an improvement in 24-hour post-dose FEV1 compared with placebo of 133, 127, 68, and 74 mL, respectively (P < .05). The 12-hour post-dose FEV1 for GP MDI 115.2, 57.6, 28.8, and 14.4 μg BID in the current study compared with placebo was 233, 157, 160, and 143 mL, respectively (all P < .001). It should be noted that in the current study, the screening post-bronchodilator percentage predicted FEV1 was 60.6% compared with 54% for GLOW1 and 56% for GLOW2. Such patients may be expected to demonstrate a greater post-bronchodilator response. Of further note, since subjects in the current study were required to be reversible, while most groups of COPD patients benefit clinically by typical LAMAs, subgroup data for QD umeclidinium suggest that subjects who are more reversible or who are current smokers may demonstrate somewhat greater FEV1 responses to treatment with LAMA.
In the GLOW2 study, for FEV1 AUC0–12 on Day 1, the difference from placebo for NVA237 was 159 mL, 32 mL above TIO, whereas in the current study the difference from Placebo MDI for GP MDI was 208, 155, 137, and 109 mL for 115.2, 57.6, 28.8, and 14.4 μg, respectively, in comparison to 172 mL for TIO. Also in GLOW2, the Day 1 improvement in peak FEV1 for NVA 237 compared to placebo was 200 mL, 47 mL greater than TIO. Whereas in the current study, the peak change from baseline in Peak FEV1 for GP MDI compared to Placebo MDI was 248, 180, 158, and 146 mL for 115.2, 57.6, 28.8, and 14.4 μg, respectively, in comparison with 198 mL for TIO.
Twice-daily dosing is of particular interest for a companion combination product containing glycopyrronium and the LABA formoterol fumarate, which is currently in development using the same porous-particle–based MDI technology. The use of a LAMA in combination with a LABA has been advocated in patients with COPD as airflow obstruction becomes more severe. As a co-suspension platform, the porous-particle technology produces efficient and stable single, dual, and triple combination MDIs without a coformulation induced change in aerosol performance across product types.
This study was conducted in COPD patients with demonstrated reversibility to a SAMA. Reversibility in a COPD population is variable. Many "non-reversible" patients will experience effects of smaller magnitude, but may still benefit; therefore, results should be confirmed in a broader COPD population. The study assessed the dose response following single dose administration across a wide range of GP MDI doses. For initial assessment of dose response, single dose administration is appropriate, however these findings should be confirmed.
Clinical benefits will require chronic-dosing that must be evaluated in appropriately designed longer-term studies. Finally, the relatively small sample size precludes many comparisons with the active comparator and provides limited information about associated rare events.
Discussion
The current study assessed GP administered by an MDI using a proprietary lipid-based porous-particle. The FEV1 data obtained during this study indicate that a single-dose of GP MDI yields statistically significant, dose-dependent, and clinically relevant bronchodilation at all doses compared with Placebo MDI. In terms of peak improvement in FEV1, the efficacy of GP MDI 57.6 and 115.2 μg bracketed that of TIO 18 μg. Although both GP MDI 14.4 and 28.8 μg demonstrated clinically relevant and statistically significant peak improvement in FEV1 compared with Placebo MDI, the magnitude of these improvements was numerically lower than those observed with TIO 18 μg.
The primary efficacy results are corroborated by the secondary efficacy variables: 12- and 24-hour post-dose FEV1, FEV1 AUC0–12, FEV1 AUC0–24, and FEV1 AUC12–24, with statistically significant greater mean changes from test-day baseline compared with Placebo MDI for all comparisons, with the exception of GP MDI 28.8 μg for 24-hour post-dose FEV1. Point-estimates for the majority of FEV1 parameters for GP MDI 57.6 and 115.2 μg were within ± 50 mL compared with TIO. All GP MDI doses demonstrated a rapid onset of action, and the 115.2 μg dose demonstrated a significantly faster onset than TIO 18 μg. With regard to the duration of action of GP MDI, several observations confirm that GP MDI is appropriate for twice daily (BID) dosing. For all GP MDI doses, the changes from baseline in FEV1 compared to Placebo MDI at 12 hours post-dose were appreciably greater than the changes at 24 hour post-dose, while these values were more consistent for TIO compared to Placebo MDI. Similarly, FEV1 AUC0–12 was greater than FEV1 AUC12–24 for all GP doses compared with Placebo MDI, while for TIO the difference from Placebo MDI in FEV1 AUC maintained close to 1:1 ratio across the 0- to 12- and 12- to 24-hour intervals. All doses of GP MDI were safe and well tolerated. The most frequently reported AE was dry mouth, which was reported for a similar proportion of study patients following Placebo MDI, GP MDI, and TIO (0–14.3% of patients).
Placing the data from the current study into context with those of existing glycopyrronium formulations is warranted. A 14-day PK study of NVA237 (Seebri® Breezehaler®, Novartis Europharm Limited, Horsham, West Sussex, United Kingdom) in doses of 25, 40, 100, and 200 μg found that the median time to reach maximal plasma concentration (tmax) was similar between NVA237 (5–6.5 minutes post-inhalation), to the 6 minutes for GP MDI 28.8 to 115.2 μg observed in the current study. The mean terminal elimination half-life (t1/2) of NVA237 is reported to range between 13 and 22 hours compared with 6.3 to 9.6 hours for GP MDI 28.8 to 115.2 μg. It remains subject to debate whether these PK traits are generalizable to specific benefits in lung function which favor once-daily (QD) or BID dosing.
In comparing the efficacy of GP MDI observed in the current study with that of NVA 237 50 μg administered QD in the Glycopyrronium bromide in COPD airWays clinical Study 1 (GLOW1) trial; treatment with NVA237 resulted in an improvement in 24-hr post dose FEV1 (average of mean 23 hours 15 minutes, and 23 hours 45 minutes post-dose values) of 105 mL after initial dosing compared with placebo (P < .001). In the GLOW2 study, study patients received either NVA 237 50 μg, TIO 18 μg or placebo once-daily (QD), the differences from placebo in 24-hr post-dose FEV1 after initial dosing were 91 and 83 mL for NVA 237 and TIO, respectively. For the current study, GP MDI 115.2, 57.6, 28.8, and 14.4 μg resulted in an improvement in 24-hour post-dose FEV1 compared with placebo of 133, 127, 68, and 74 mL, respectively (P < .05). The 12-hour post-dose FEV1 for GP MDI 115.2, 57.6, 28.8, and 14.4 μg BID in the current study compared with placebo was 233, 157, 160, and 143 mL, respectively (all P < .001). It should be noted that in the current study, the screening post-bronchodilator percentage predicted FEV1 was 60.6% compared with 54% for GLOW1 and 56% for GLOW2. Such patients may be expected to demonstrate a greater post-bronchodilator response. Of further note, since subjects in the current study were required to be reversible, while most groups of COPD patients benefit clinically by typical LAMAs, subgroup data for QD umeclidinium suggest that subjects who are more reversible or who are current smokers may demonstrate somewhat greater FEV1 responses to treatment with LAMA.
In the GLOW2 study, for FEV1 AUC0–12 on Day 1, the difference from placebo for NVA237 was 159 mL, 32 mL above TIO, whereas in the current study the difference from Placebo MDI for GP MDI was 208, 155, 137, and 109 mL for 115.2, 57.6, 28.8, and 14.4 μg, respectively, in comparison to 172 mL for TIO. Also in GLOW2, the Day 1 improvement in peak FEV1 for NVA 237 compared to placebo was 200 mL, 47 mL greater than TIO. Whereas in the current study, the peak change from baseline in Peak FEV1 for GP MDI compared to Placebo MDI was 248, 180, 158, and 146 mL for 115.2, 57.6, 28.8, and 14.4 μg, respectively, in comparison with 198 mL for TIO.
Twice-daily dosing is of particular interest for a companion combination product containing glycopyrronium and the LABA formoterol fumarate, which is currently in development using the same porous-particle–based MDI technology. The use of a LAMA in combination with a LABA has been advocated in patients with COPD as airflow obstruction becomes more severe. As a co-suspension platform, the porous-particle technology produces efficient and stable single, dual, and triple combination MDIs without a coformulation induced change in aerosol performance across product types.
Study Limitations
This study was conducted in COPD patients with demonstrated reversibility to a SAMA. Reversibility in a COPD population is variable. Many "non-reversible" patients will experience effects of smaller magnitude, but may still benefit; therefore, results should be confirmed in a broader COPD population. The study assessed the dose response following single dose administration across a wide range of GP MDI doses. For initial assessment of dose response, single dose administration is appropriate, however these findings should be confirmed.
Clinical benefits will require chronic-dosing that must be evaluated in appropriately designed longer-term studies. Finally, the relatively small sample size precludes many comparisons with the active comparator and provides limited information about associated rare events.
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