An investigative closed triple combination therapy by GSK is for people with COPD and includes three medications: an inhaled corticosteroid called fluticasone; umeclidinium, a LAMA (long-acting muscarinic antagonist); and vilanterol, a LABA (long-acting beta2-adrenergic agonist).

The drug combination would be delivered once-daily in GSK’s Ellipta dry powder inhaler.

GSK filed a New Drug application to the U.S. Food and Drug Administration (FDA) in November 2016 for the triple combo therapy, based on results from the triple combination therapy development program and from study data from fluticasone, umeclidinium, and vilanterol alone.

The combination is being developed to provide a new treatment option for the management of advanced COPD, according to recently updated GOLD strategy guidelines.

How does the triple combo therapy for COPD work?

The mechanism of action of the triple combination is based on how each of the substances work.

Fluticasone is a synthetic trifluorinated corticosteroid with anti-inflammatory activity that works to reduce airway swelling.

The anti-inflammatory activity of fluticasone aims to alter the development of COPD, although the precise mechanism by which it does so is not fully understand. In this disease, the major inflammatory agents include multiple cell types (mast cells, eosinophils, neutrophils, macrophages and lymphocytes) and mediators (histamine, eicosanoids, leukotrienes and cytokines). Corticosteroids have been shown to have a wide range of actions on these cell types and mediators are involved in inflammation.

Umeclidinium is a long-acting muscarinic antagonist, also known as an anticholinergic. It connects to the muscarinic receptors subtypes M1 to M5. The M3 receptors are located in the muscle of the bronchi and are responsible for bronchoconstriction. As umeclidinium has affinity to the M3 receptors, it works by inhibiting them on the muscle of the bronchi, leading to bronchodilation.

Vilanterol is a LABA, and its effects are due to the stimulation of an enzyme called adenyl cyclase in smooth muscle cells of the lungs. This enzyme helps convert adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). When the levels of cAMP increase, bronchial muscle cells relax and the release of mediators of immediate hypersensitivity, especially from mast cells, are effectively blocked.

Triple combination studies in people with COPD

A Phase 3a study (NCT02345161) to assess the efficacy, safety and tolerability of the once-daily fixed dose triple combination of fluticasone, umeclidinium and vilanterol (FF/UMEC/VI) in people with COPD has been completed.

This 24-week study compared the triple combo therapy to the combination of budesonide and formoterol (Symbicort).  Statistically significant improvements were seen in the triple combination compared with Symbicort regarding lung function (measured by trough FEV1) and health-related quality of life, as measured by the St. George’s Respiratory Questionnaire (SGRQ).

A phase 3b study (NCT02729051) is currently ongoing. The 24-week randomized, double-blind study is comparing the triple combination (FF/UMEC/VI) with an “open” triple therapy in people with COPD. The open triple therapy consists of the administration of two separate medicines, the combination fluticasone and vilanterol, along with umeclidinium. The primary objective is a change in lung function as measured by trough FEV1 at 24 weeks. Secondary endpoints include health-related quality of life, time to first moderate or severe exacerbation, transitional dyspnea index, number of participants with adverse events, and number of participants with abnormal blood levels.

The estimated completion date for this study is May 2017.

A 52-week phase 3 study (NCT02164513) is also ongoing, and is assessing the effectiveness of the triple combination therapy in reducing the annual rate of moderate and severe exacerbations compared with the dual therapy fluticasone – vilanterol or umeclidinium – vilanterol in people with COPD. The estimated completion date is July 2017.

The primary objective is the number of moderate and severe exacerbations. Secondary objectives include lung function measures, health-related quality of life, time to first exacerbation and number of exacerbations.

A Phase 4 study (NCT02982187) is currently recruiting participants and will assess the benefits of delivering the triple therapy using Ellipta dry-powder inhaler compared to two other types of dry-powder inhalers. This study will measure the number of participants who make at least one critical error after reading the patient information leaflet (primary objective), and being instructed by the healthcare provider (secondary objective).

 

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