Benefits of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI) in improving lung function and reducing exacerbations in patients with moderate-to-very severe COPD: a pooled analysis of the PINNACLE studies

Reducing the future risk of chronic obstructive pulmonary disease (COPD) exacerbations is one of the main goals for the treatment of the disease [1]. Exacerbations cause a substantial impact on patients’ lives; they are associated with a greater rate of lung function decline [2] and worse quality of life [3] compared with patients who do not experience exacerbations. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2020 report recommends long-acting muscarinic antagonist (LAMA)/long-acting β₂-agonist (LABA) combinations for prevention of exacerbations in some patients, prior to escalation to triple therapy [1]. However, there are limited data regarding the benefit of LAMA/LABA fixed-dose combinations (FDCs) versus the corresponding monocomponents in reducing exacerbations in patients with COPD [4‐6].

Glycopyrrolate/formoterol fumarate metered dose inhaler 18/9.6 μg (GFF MDI; Bevespi Aerosphere®), an FDC of the LAMA glycopyrrolate and the LABA formoterol fumarate, delivered using innovative co-suspension delivery technology, is approved as a maintenance treatment for COPD. The efficacy and safety of GFF MDI compared with its respective monocomponents have been demonstrated in patients with moderate-to-very severe COPD in the pivotal Phase III studies PINNACLE-1, PINNACLE-2, and PINNACLE-4 (NCT01854645, NCT01854658, and NCT02343458; all 24 weeks), and PINNACLE-3 (NCT01970878; 28-week safety extension study of PINNACLE-1 and -2), in patients from the USA, Asia, Europe, Australia, and New Zealand [7‐9]. However, the individual pivotal studies, which were not enriched for patients with a high risk of exacerbations, were not sufficiently powered to interrogate the impact of GFF MDI on exacerbations. Yet, a pooled analysis of these studies provides a reasonably large body of evidence in which to assess the exacerbation benefits of GFF MDI.

The objective of this pre-specified, integrated analysis of individual patient data from the three 24-week studies, PINNACLE-1, -2, and -4, was to further evaluate the efficacy of GFF MDI, by using the combined data set to provide a more precise estimation of the treatment effects on lung function, COPD exacerbations, and clinically important deterioration (CID) endpoints in the pooled population, and to evaluate safety in a large patient population.

This pooled analysis of data from PINNACLE-1, -2, and -4 illustrates consistent lung function benefits across the individual studies, with improvements in the change from baseline in morning pre-dose trough FEV₁ at week 24 and over 24 weeks with GFF MDI versus placebo MDI exceeding the MCID of 100 mL [12]. GFF MDI also consistently provided significant improvements in trough FEV₁ and peak change from baseline in FEV₁ within 2 h post-dose compared with GP MDI and FF MDI [7, 9]. Improvements in lung function in the PINNACLE studies were generally similar to those reported in other pivotal studies of LAMA/LABA FDCs [10, 11, 13]. A network meta-analysis performed using all available data of fixed-dose LAMA/LABA combinations (including the PINNACLE studies) also found that GFF MDI had comparable efficacy to other LAMA/LABAs in improving lung function [14].

Pooling data across the three pivotal PINNACLE studies allowed for assessment of study endpoints, which were not well powered in the individual studies, such as differential treatment effects on COPD exacerbations. Many studies assessing COPD symptom and exacerbation endpoints enroll patients with a high symptom burden or exacerbation history [10, 11, 15] to observe more substantial treatment effects. Notably, even though the PINNACLE studies did not enrich the patient population for these characteristics, clinically meaningful reductions in the risk of a moderate or severe COPD exacerbation, treatment failure, and CID were observed with GFF MDI compared with GP MDI, FF MDI, and placebo MDI in the pooled ITT population.

Given that the inclusion criteria of the PINNACLE studies did not enrich the study population for patients with a high symptom burden or exacerbation history, the integrated analyses included subgroups that examined the impact of two risk factors for exacerbations (high symptom burden [CAT score ≥15] and/or a recent exacerbation history [≥1 moderate or severe exacerbations in the past year]) on treatment benefit. While the GOLD report uses a cut-off of CAT ≥10 to define symptomatic patients [1], this pooled analysis defined the symptomatic population as CAT ≥15 based on the threshold pre-specified in the PINNACLE-4 analysis plan. Previous pooled findings from PINNACLE-1 and -2 have shown that results for CAT ≥10 and CAT ≥15 subgroups were generally similar [6]. Exacerbation reductions for GFF MDI versus monocomponents were greater in symptomatic patients and those with a previous exacerbation history compared to the pooled ITT population (as indicated by smaller hazard ratios), suggesting that these subgroups of patients may derive an even larger benefit from LAMA/LABA treatment compared with monotherapies. The pooled ITT and symptomatic populations experienced similar treatment benefits with regard to the time to first CID. However, this was not unexpected considering that the time to first CID was primarily driven by the ≥100 mL decline in morning pre-dose trough FEV_1, and a previous analysis of pooled data from PINNACLE-1 and -2 showed that the magnitude of improvement in the morning pre-dose trough FEV₁ was independent of patient baseline CAT scores [6], and would also not be expected to relate to exacerbation history.

The exacerbations treatment pathway described in the GOLD 2020 Report recommends dual LAMA/LABA combination therapy for patients in whom an individual LAMA or LABA is not adequately controlling COPD exacerbations unless they have a blood eosinophil count ≥300 cells/μL or a high risk of further exacerbations [1]. The decreased risk of exacerbations demonstrated with GFF MDI relative to GP MDI and FF MDI in patients with moderate-to-very severe COPD from the PINNACLE studies supports this treatment recommendation. However, the comparable safety profile between GFF MDI, GP MDI and FF MDI, and the fact that treatment differences in exacerbation risk were observed even in a population including low-risk patients, supports the use of dual LAMA/LABA therapy regardless of patients’ symptom burden and exacerbation history in order to reduce the chance of experiencing an exacerbation that could substantially impact their lung function and quality of life [2, 3].

The PINNACLE studies also assessed dyspnea using the transition dyspnea index (TDI) scale [9, 16]. However, it was not feasible to pool these data, as PINNACLE-1 and -2 used a self-administered computerized (SAC) version of the tool, while PINNACLE-4 used the more established paper interviewer-administered version, and thus this endpoint was not included in the pooled analysis. The SAC TDI is reported on a continuous scale, while the interviewer-administered TDI is on an integer Likert scale [17‐19]. All three PINNACLE studies assessed quality of life using the SGRQ [7, 9], although a pooled analysis was not considered useful due to variation in the findings between PINNACLE-1 and -2 versus PINNACLE-4. The changes from baseline in SGRQ total score at week 24 with all active treatments were greater in PINNACLE-4 than in PINNACLE-1 and -2 [7, 9], which may relate to the geographic difference in the populations studied and the modifying effect of socioeconomic status on quality of life outcomes [20].

The analysis of pooled safety data enabled the safety and tolerability of GFF MDI to be investigated in a much larger patient population than any of the individual studies alone. The results in the pooled population were commensurate with the individual studies [7, 9], and demonstrated that all treatments were well tolerated, with no unexpected safety signals identified.

Limitations of the analyses include the fact that the three individual studies were produced at different times and, accordingly, some of the pooled analyses were specified after results from PINNACLE-1 and -2 were available (but before the unblinding of PINNACLE-4 data). It should be noted that GFF MDI and the comparators used in the PINNACLE studies were all formulated using co-suspension delivery technology (other than tiotropium in PINNACLE-1). Hence, these studies could not assess the potential impact of the co-suspension delivery technology on clinical outcomes.

While many studies that evaluate COPD exacerbations are conducted over 52 weeks [15, 21, 22], the PINNACLE studies were 24 weeks in duration. However, due to the large number of patients (n = 4983) and patient-years of exposure (> 2000), the fact that patients were recruited across all four seasons of the year in each study, and the use of time-to-event analyses to handle censoring due to study discontinuation following a COPD exacerbation, this pooled analysis provides a compelling body of evidence for the benefit of GFF MDI in preventing exacerbations.

Pooled analyses of lung function endpoints (pre-dose trough FEV₁ and peak FEV₁) from the PINNACLE studies supported the findings from the individual studies, with GFF MDI 18/9.6 μg demonstrating significant, clinically meaningful improvements versus placebo and monocomponents in patients with moderate-to-very severe COPD. GFF MDI reduced the risk of moderate or severe COPD exacerbations, CID, and treatment failure compared with monocomponents and placebo MDI, even in a patient population that was not enriched for symptoms or exacerbation history. Treatment benefits for GFF MDI versus monotherapies on exacerbation risk were generally even greater in subgroups of patients with higher symptom burden (CAT score ≥15) and those with an exacerbation history (≥1 moderate or severe exacerbation in the past year), providing additional support for the importance of LAMA/LABA therapy in these patient populations.