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Differentiating triple therapy options in COPD

Prof. Paul Jones
Global Medical Expert for the Global Respiratory Franchise
GlaxoSmithKline
Dr. Raj Sharma
PhD in Respiratory Pharmacology
Global Medical Affairs Lead Inhaled Delivery Systems and CIS (Connected Inhaler System)
GlaxoSmithKline
09 Nov 2020

Guidelines recommend triple therapy with an inhaled corticosteroid (ICS), a long-acting muscarinic antagonist (LAMA) and a long-acting β-agonist (LABA) for symptomatic patients with chronic obstructive pulmonary disease (COPD) exacerbations despite treatment with dual therapy. In a recent webinar, Professor Paul Jones and Dr Raj Sharma from GlaxoSmithKline reviewed the benefits and risks of triple therapy, and discussed how using a single, effective inhalation device for triple therapy can reduce exacerbations.

The Global Strategy for the Diagnosis, Management and Prevention of COPD (GOLD) 2020 report recommends dual therapy with ICS/LABA or LAMA/LABA as initial treatment for high-risk (Group D) patients with severe symptoms. “Patients with exacerbations despite initial treatment are considered to have treatment failure, for which the guideline recommends escalation to triple therapy with ICS/LAMA/LABA,” said Jones. [https://goldcopd.org/gold-reports/]

Triple therapy reduces exacerbations vs dual therapy

The phase III, randomized, double-blind IMPACT study compared 52 weeks of once-daily triple therapy with fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) 100/62.5/25 µg with the dual therapies FF/VI 100/25 µg and UMEC/VI 62.5/25 µg in 10,355 patients with moderate-to-severe COPD. Each regimen was administered via a single dry-powder inhaler (DPI). “By adding LAMA [ie, UMEC] to dual ICS/LABA therapy [ie, FF/VI], the annual rate of exacerbation was significantly reduced by 15 percent [p<0.001], whereas adding ICS [ie, FF] to dual LAMA/LABA therapy [ie, UMEC/VI) led to an even more pronounced 25 percent reduction [p<0.001],” remarked Jones. [N Engl J Med 2018;378:1671-1680]

The phase III, randomized, double-blind FULFIL study also demonstrated the efficacyof triple therapy in patients with advanced COPD (n=1,810). After 24 weeks of treatment, moderate/severe exacerbation rate was reduced by 35 percent (p=0.002) with once-daily FF/UMEC/VI 100/62.5/25 µg triple therapy vs twice-daily budesonide (BUD)/formoterol (FOR) 400/12 µg dual therapy. At the end of a 52-week extension phase, in which 430 patients remained on blinded treatment, the rate reduction was 44 percent with triple vs dual therapy (ratio, 0.56; 95 percent confidence interval, 0.37 to 0.85). [Am J Respir Crit Care Med 2017;196:438-446]

“Evidence has shown that greater bronchodilation with dual bronchodilator results in fewer exacerbations per year. This explains the differences in reduction of exacerbations between the two therapies,” commented Jones. [Pulm Pharmacol Ther 2018;49:11-19]

Differences between drug molecules

“Different drug molecules within the same class may vary in efficacy in COPD treatment,” commented Jones. A phase IIIb, randomized, double-blind study that compared two LAMA/LABA therapies in 1,119 patients with moderate-to-very-severe COPD showed that once-daily UMEC/VI was more efficacious than twice-daily glycopyrrolate (GLY)/formoterol fumarate (FOR) in improving lung function (least square [LS] mean difference in pre-dose trough forced expiratory volume in 1 second [FEV1], -87.2 mL) after 24 weeks of treatment. [Adv Ther 2019;36:2434-2449]

A randomized, double-blind study involving 1,017 patients with COPD demonstrated superior efficacy of UMEC 62.5 µg vs tiotropium (TIO) 18 µg in improving lung function. At day 84, improvements in weighted mean FEV1 over 0–12 hours post-dose were similar between the two treatment arms, but were significantly greater with UMEC vs TIO over 12–24 hours post-dose (70 mL; p=0.015). [Int J Chron Obstruct Pulmon Dis 2016;11:719-730]

Similarly, once-daily UMEC/VI 62.5/25 µg demonstrated superior efficacy over once-daily TIO/olodaterol (OLO) 5/5 µg in improving lung function in a randomized, two-period crossover, head-to-head study involving 236 patients with moderate-to-severe COPD. A statistically significant increase in trough FEV1 from baseline was observed with UMEC/VI vs TIO/OLO after 8 weeks of treatment (LS mean difference, 53 mL; p<0.001), with 52 percent vs 19 percent of patients achieving a clinically meaningful increase (100 mL) in trough FEV1 from baseline. [Adv Ther 2017;34:2518-2533]

“Different glucocorticoid molecules also vary in anti-inflammatory effects,” pointed out Jones.  “With a single dose of FF/VI in ICS-naïve asthma patients, bronchodilation was maintained for 72 hours post-dose, with a long anti-inflammatory effect of FF [in terms of reduction in exhaled nitric oxide] exceeding 48 hours, which is not commonly observed with other ICS.” [Respir Res 2018;19:133]

In the real-world, open-label, randomized controlled Salford Lung Study, which evaluated the effectiveness and safety of FF/VI in everyday clinical practice using electronic health records of 2,802 adults with COPD, a significant reduction (LS mean annual rate, 10.1 percent; p=0.018) in moderate/severe exacerbation rate was observed with once-daily FF/VI vs twice-daily fluticasone propionate (FP)/salmeterol. [Respir Med 2019;147:58-65]

In addition, FF showed greater airway potency and a wider therapeutic index than FP and BUD in an escalating-dose, placebo-controlled, crossover study in 54 patients with asthma. FF also provided more protection against airway hyperresponsiveness, with less systemic activity than FP or BUD. [Br J Clin Pharmacol 2020;1-11]

Benefits and risks of the ICS component in triple therapy

“Significantly improved outcomes are observed when ICS is added to dual bronchodilator therapy. In the IMPACT study, FF/UMEC/VI was associated with a 34 percent [p<0.001] reduction in the annual rate of severe exacerbations leading to hospitalization vs UMEC/VI. FF/UMEC/VI also demonstrated a 28 percent [p=0.042] risk reduction in all-cause mortality vs UMEC/VI in the post hoc analysis of IMPACT,” said Jones. [N Engl J Med 2018;378:1671-1680; Lipson DA, et al, ATS 2019, poster 221]

Despite its efficacy in COPD management, ICS has been associated with a risk of pneumonia that has caused concerns. However, the IMPACT study showed that the proportion of patients hospitalized with pneumonia were comparable between the dual bronchodilator and the ICS-containing regimens (3 percent with UMEC/VI vs 4 percent each with FF/UMEC/VI and FF/VI). [N Engl J Med 2018;378:1671-1680]

“Rates of pneumonia from different studies cannot be compared directly because many factors could affect the rates. The only way to compare the ratio of pneumonia rates between the ICS-containing and the dual bronchodilator regimens is within a study. The IMPACT study showed an approximately 50 percent increase in pneumonia risk with FF-containing regimens relative to UMEC/VI, and the ETHOS study showed a similar increase with BUD-containing regimens. From these data, we can conclude that pneumonia is a class effect seen with all ICS,” commented Jones. “Although the risk of pneumonia is increased with ICS, the risk of mortality is reduced.” (Figure 1) [N Engl J Med 2020;383:35-48; N Engl J Med 2018;378:1671-1680]

HK-GLA-378_01

Inhaler technique affects clinical outcomes

“The global burden of COPD remains high despite the development of new inhaler devices in the last few decades to enhance drug delivery and reduce side effects. One reason may be related to poor inhaler technique. Global guidelines recommend regular assessment of inhaler technique and, in particular, before escalation of therapy,” noted Sharma. [https://goldcopd.org/gold-reports/; https://ginasthma.org/gina-reports/]

“Poor inhaler technique affects dose delivery and results in worsening outcomes, such as increased risk of hospitalization, emergency room visits, oral corticosteroid use and antimicrobial use. Unfortunately, in routine clinical practice, more than two-thirds of patients make at least one error, on average, when using an inhaler device,” said Sharma [Respir Med 2011;105:930-938; Eur Respir J 2017;49:1601794]

Apart from inhaler technique, several factors influence dose delivery and lung deposition that could contribute to local efficacy and systemic effects of a drug. These include factors related to inhaler devices (particle size, consistency of dose, formulation, resistance), airway anatomy and physiology (morphology, size, lung function, state of disease), and inhalation manoeuvre (peak inspiratory flow, inhaled volume, breath-holding period). [Arch Bronconeumol 2012;48:240-246; Annu Rev Biomed Eng 2008;10:195-220; Respir Med 2008;102:593-604]

“The Ellipta DPI device has demonstrated consistent dose delivery across disease severities. More than 90 percent of the target dose of all component molecules can be delivered at a peak inspiratory flow rate [PIFR] of 30 L/min,” noted Sharma. [Prime D, et al, ERS 2019, poster PA4230] “Although patients with increasing COPD severity have reduced inhalation capability, real-world data indicate that over 99 percent of COPD patients are able to achieve the PFIR required to use the Ellipta DPI.” (Figure 2) [Mularski RA, et al, ATS 2020, poster P1045]

HK-GLA-378_02

“Using multiple inhaler types can be confusing for patients. Ellipta is a suitable device for administering all three drugs at the same time, thereby improving adherence. Compared with other commonly used COPD inhalers, Ellipta is associated with a much lower critical error rate and is preferred by more patients because of its ease of use. Most patients can use it correctly within 5 minutes with instructions from healthcare providers, while it could take up to 25 minutes for other inhaler types, especially with multiple inhalers,” said Sharma.

Conclusion

Triple therapy is recommended for high-risk patients with COPD who failed dual therapy. Once-daily FF/UMEC/VI has demonstrated clear clinical benefits over dual therapies, including once-daily and twice-daily ICS/LABA and once-daily LAMA/LABA, in terms of risk reduction of exacerbations and mortality, without a worsened risk-benefit profile. Ellipta DPI is a suitable device for consistent dose delivery of triple therapy, and may improve adherence and optimize patient outcomes.

 

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