People with uncontrolled asthma generally have an increased risk of exacerbation, experience lower quality of life, and are at increased risk of hospitalization and death.1,2 The level of asthma severity varies by demographic characteristics (Figure 13); across the United States, the level of uncontrolled asthma among all people with asthma varies by state, from 52.4% in Massachusetts to 73.3% in Missouri.3 Although the population of adults with uncontrolled asthma accounts for fewer than 5% of all asthma patients, they incur more than 50% of asthma-related healthcare costs.4,5 Asthma-related deaths are highest in those aged 65 years and older.6,7 Uncontrolled asthma is a significant economic burden and compromises health-related quality of life.8-10

Most people with asthma can be effectively managed with an inhaled corticosteroid (ICS), alone or in combination with a long-acting β2-agonist (LABA). However, a significant number of patients with moderate or severe asthma remain symptomatic and inadequately controlled with optimized high-dose ICS+LABA combination therapy despite good adherence and proper inhalation technique, in addition to controlling risk factors and comorbidities.11,12 Effective step-up treatments in the setting of high-dose ICS+LABA therapy is an unmet need. 

A recently approved triple-therapy combination — fluticasone furoate, umeclidinium, and vilanterol (FF+UMEC+VI) — in a single inhaler was found to be associated with improved asthma control in patients whose asthma remained uncontrolled with medium- or high-dose ICS+LABA treatment.12 The approval of this combination therapy provides a welcome addition to treatment options for patients with uncontrolled asthma, but unique challenges and unanswered questions that deserve additional research have emerged:

• How should patients be selected for treatment?
• When should treatment be stepped up or stepped down?
• Can biomarkers play a role in treatment optimization?

This review focuses on the subgroup of patients with an asthma phenotype predisposed to poor control with a conventional treatment strategy; the rationale for a single-inhaler, triple-therapy combination for this population; and evidence supporting approval of the single-inhaler combination triple therapy for clinical use.

Why knowledge of asthma phenotypes is critical to the treatment approach

Asthma is a heterogeneous condition; not all patients respond the same way to the same treatment. In some patients, eosinophilic airway inflammation and asthma symptoms increase in parallel, and treatment with an ICS mirrors a stepwise approach. In other patients, there is little evidence of eosinophilic inflammation despite asthma symptoms; increasing the ICS dosage does not alleviate symptoms but might increase adverse effects of the drug. In still other patients, high eosinophilic inflammation might produce few symptoms.

Each of these phenotypes requires a specific treatment approach. Stratifying patients according to phenotype therefore allows for better selection of available therapies.13

In characterizing asthma as a T-helper 2 (Th2) immunologic disease, 2 major subtypes of severe asthma, characteristic of uncontrolled disease, have been identified: T2-high asthma and T2-low asthma. T2-high asthma is associated with increased epithelial expression of Th2-type cytokines, such as interleukin (IL)-4, IL-5, and IL-13. In contrast, T2-low asthma is characterized by the absence of markers of Th2-mediated inflammation, recurrent bacterial or viral infection, an altered innate immune response, and airway remodeling.4

There are no specific biomarkers that can differentiate T2-high asthma and T2-low asthma. Surrogate markers, based on cut-off points for the immunoglobulin E (IgE) level, blood eosinophil count, and fraction of exhaled nitric oxide, are used to define T2-high disease (specifically, elevation of ≥2 markers: IgE ≥100 IU/mL; blood eosinophil count ≥300/μL; exhaled nitric oxide fraction ≥30 ppb) or T2-low asthma (elevation of 1 marker or no elevated markers).4 Patients with T2-high severe asthma can be differentiated as predominantly allergic or eosinophilic based on specific clinical features (Table 1).4

In everyday clinical practice, stratifying patients with asthma using specific clinical features and biomarkers, as summarized in Table 1, allocates most patients to either allergic-predominant or eosinophilic-predominant T2-high asthma to allow selection of appropriate treatment.4 For example, the anti-IgE agent omalizumab is the treatment of choice for a patient with allergic-predominant severe asthma, whereas an anti-IL-5 agent is a reasonable agent for a patient with eosinophilic-predominant asthma.14 For patients with an overlap phenotype, starting with either an anti-IgE or anti-IL-5 agent is reasonable.15
The complex phenotypes of severe asthma emphasize the need for a personalized asthma treatment approach, as advocated by the Global Initiative for Asthma (GINA) treatment recommendations.16

Can current treatment options meet the needs of patients with severe uncontrolled asthma?

GINA recommendations for patients with uncontrolled asthma (Step 3 to Step 5; Figure 2)16 is a stepwise increase in the dosage of an inhaled ICS+LABA combination. Despite maximized ICS+LABA therapy, however, 30% to 50% of patients with moderate or severe asthma remain inadequately controlled. More than 45% of patients with asthma at GINA Steps 4 and 5 remain uncontrolled, even with optimal adherence and correct inhaler use.12,17,18

To address the unmet need for improved step-up therapy for this population, several new drugs, including biologics, have been approved that target underlying asthma pathophysiology, including:

• Tiotropium, a long-acting muscarinic antagonist (LAMA);
• Omalizumab, an anti-IgE agent; and
• Anti-IL-5 agents (mepolizumab, reslizumab, benralizumab).

Some of these agents, such as tiotropium and omalizumab, are included as new add-on treatments in GINA Steps 4 and 5 recommendations in adults and adolescents 12 years of age and older (Figure 2).16 Although biologics can reduce exacerbations in patients with T2-high inflammation whose asthma is severe and uncontrolled, these drugs are generally less consistent in improving lung function and alleviating symptoms. GINA guidelines recommend adding tiotropium before escalating treatment to a biologic or a low-dose oral corticosteroid in patients aged 12 years and older whose asthma is not well controlled with an ICS+LABA combination.16
Evidence for the effectiveness of adding a LAMA to an ICS+LABA combination to reduce exacerbations in patients with difficult-to-treat asthma was demonstrated in several observational and randomized studies.19-22 A systematic review and meta-analysis of 15 randomized clinical trials involving 7122 patients with controlled asthma found that adding a LAMA to an ICS+LABA combination significantly lowered the risk of worsening asthma.23 Although addition of a LAMA to ICS+LABA combination therapy has demonstrated improved outcomes in patients with severe uncontrolled asthma, delivery of triple therapy requires an innovative approach to avoid having the patient use 2 inhalation devices.

Single-inhaler triple therapy might offer a solution for patients with severe, uncontrolled asthma

Proof of concept, showing the effectiveness of a single inhaler with a 3-medication combination in patients whose asthma remained uncontrolled despite high doses of ICS plus LABA, was demonstrated in 2 concomitant studies.24,25 TRIMARAN ( Identifier: NCT02676076) included patients receiving medium-dose ICS+LABA and evaluated the triple-agent combination beclomethasone, formoterol, and glycopyrronium (100-6-12.5 µg twice daily) against beclomethasone plusformoterol. In TRIGGER ( Identifier: NCT02676089), glycopyrronium was added to high-dose ICS+LABA treatment (200-6-12.5 µg twice daily).24,25
Pooled results from the 2 studies showed that triple therapy in a single fixed combination significantly reduced the rate of severe asthma exacerbation and was associated with reduced treatment with systemic steroids in patients whose asthma was uncontrolled on medium- or high-dose beclomethasone dipropionate plus formoterol furoate.24,25 Based on the results of TRIMARAN and TRIGGER, several triple combinations of a LAMA with an ICS+LABA combination in a single inhalation device have been evaluated and approved (Table 224,26,27). To date, fluticasone furoate, umeclidinium, and vilanterol combination therapy in a single inhalation device is approved in the United States.

CAPTAIN ( Identifier: NCT02924688) was a phase 3, randomized, double-blind, active-controlled, 6-arm, parallel-group, global multicenter study that evaluated a combination of 3 therapies — fluticasone furoate, umeclidinium, and vilanterol (FF+UMEC+VI) — in a single inhaler.12 FF+UMEC+VI (delivered at 100-25-62.5 μg, 200-25-62.5 μg, 100-25-31.25 μg, or 200-25-31.25 μg) was compared to FF+VI (100-25 μg and 200-25 μg) given once daily to patients whose asthma was inadequately controlled despite treatment with an ICS+LABA (>250 μg/d fluticasone propionate or equivalent) maintenance asthma medication.
Overall, results of CAPTAIN showed that triple therapy of FF+UMEC+VI delivered via a single inhaler reduces airflow obstruction and improves asthma control in patients whose asthma is inadequately controlled on an ICS+LABA, without additional safety concerns.12 The higher dose of fluticasone furoate was found to reduce the exacerbation rate, particularly in patients with elevated biomarkers of T2 airway inflammation.
Based on the results from CAPTAIN, FF+UMEC+VI inhalation powder was approved by the US Food and Drug Administration in September 2020 as the first single-inhaler, once-daily triple therapy for maintenance treatment of asthma in patients aged 18 years and older who are inadequately controlled on an ICS+LABA. FF+UMEC+VI is approved at 2 dosage combinations: 100-25-62.5 μg and 200-25-62.5 μg.28

FF+UMEC+VI adverse effects
FF+UMEC+VI adverse effects
Adverse effects commonly reported include pharyngitis/nasopharyngitis, upper respiratory tract infection/viral upper respiratory tract infection, bronchitis, sinusitis, urinary tract infection, rhinitis, influenza, headache, and back pain.

Three agents in a single inhaler has several advantages over separate inhalers, including potential cost savings, and patients with good treatment adherence can have improved asthma control.
“Asthma combination therapy delivered via single rather than separate inhalers is recommended to increase adherence since it can be somewhat cumbersome to use separate inhalers,” said Mario Cazzola, MD, Honorary Professor of Respiratory Medicine at the University of Rome, Italy. “Furthermore, it can also reduce the possibility of LABA overuse and ICS underuse, which have the potential to cause serious adverse effects. This means that the use of ICSs, LABAs, and LAMAs in separate inhalers by patients who may present varying symptoms and inflammation should always be discouraged,” Dr Cazzola added.
Although triple therapy in a single inhaler is a positive addition to treatment options for patients with severe uncontrolled asthma, clinical questions persist. Although the GINA strategy recommends triple therapy in severe asthma before escalating to treatment with a biologic or low-dose oral corticosteroid, it also emphasizes that asthma severity can change over time. Therefore, intensity of treatment must change with asthma severity. Consequently, questions arise about what the indicators are for stepping up or stepping down treatment.
“The goal of therapy,” Dr Cazzola said, “is to offer the patient the minimum level of therapy capable of maintaining asthma control. This means that de-escalation of triple therapy is often a need, but it could be problematic, especially in patients who if well controlled will be reluctant to stop a treatment that they perceive effective.”
It is also unclear how to identify patients who can benefit from single-inhaler triple therapy, which is important to minimize the risk of indiscriminate use and a one-size-fits-all treatment approach. This is an important concern, given that in CAPTAIN, the effects of adding umeclidinium and increasing the dose of fluticasone furoate differed by biomarkers of T2 airway inflammation, suggesting that different treatable traits are associated with different outcomes.12 Using biomarkers and clinical features to identify “treatable traits” might be an approach to improve patient selection and guide more effective use of add-on inhaled therapy in this patient population, although more research is needed.
“In my opinion, airflow limitation and small airway disease must be considered treatable traits,” said Dr Cazzola. “Consequently, triple therapy should start earlier than currently recommended by GINA to optimize bronchodilation and, mainly, reduce lung hyperinflation, which means improved asthma control and also the possibility of influencing neuronal plasticity.”

Clinical applicability

Most patients with asthma respond well to available treatment with an ICS+LABA. However, a minority of patients do not respond to treatment and have uncontrolled asthma. Patients with uncontrolled asthma have unmet medical needs, and managing these patients can be challenging. Approval of FF/UMEC/VI triple combination therapy in a single inhaler provides a new step-up treatment option for patients with uncontrolled asthma despite maximized ICS+/LABA combination therapy.

Individualized treatment remains critical to ensure that patients are selected for treatment appropriately, as does patient education on proper inhaler technique and the importance of adherence to therapy.


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Reviewed February 2021