GlaxoSmithKline plc and Innoviva, Inc. announced the presentation of further data from the pivotal phase III FULFIL study with investigational closed triple combination therapy fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI 100/62.5/25 mcg) in patients with chronic obstructive pulmonary disease (COPD), at the European Respiratory Society International Congress taking place in London this week.

The FULFIL study was designed to evaluate the effects of once daily FF/UMEC/VI compared with twice daily Symbicort Turbohaler (budesonide/formoterol 400/12 mcg) in patients with advanced COPD.

The study, which reported headline results in June 2016, met its two co-primary endpoints. At 24 weeks, there was a clinically meaningful and statistically significant (p<0.001) benefit for FF/UMEC/VI in both lung function, measured as mean change from baseline in trough FEV1 (171mL, 95% confidence interval [148, 194]) and health-related quality of life, measured as mean change from baseline in St George’s Respiratory Questionnaire (SGRQ) total score (-6.6 units for closed triple versus -4.3 units for budesonide/formoterol, difference of -2.2 units, 95% confidence interval [-3.5, -1.0]). In addition, the proportion of patients who responded with the minimum clinically important difference in SGRQ (-4 units) was 50% on closed triple and 41% on budesonide/formoterol (odds ratio 1.41; p<0.001).

This benefit of treatment with closed triple therapy was also observed in the subset of patients who received treatment for up to 52 weeks, with a statistically significant improvement of 179ml in trough FEV1 and a numerical improvement of -2.7 units in SGRQ total score at week 52 with closed triple therapy compared with budesonide/formoterol.

The study also showed a statistically significant and clinically meaningful reduction in the annual rate of moderate/severe exacerbations with closed triple therapy compared to budesonide/formoterol, with closed triple therapy showing a 35% reduction versus budesonide/formoterol based on data up to 24 weeks (p=0.002) and a 44% reduction in the subset of patients that received treatment for up to 52 weeks (p=0.006).

The safety profile of the closed triple combination up to 24 weeks and in the subset of patients up to 52 weeks was consistent with the known profile of the individual medicines and their combinations. Up to both 24 weeks and 52 weeks, the most common adverse events in both treatment arms were nasopharyngitis, headache and COPD worsening.

The incidence of investigator-reported serious adverse events for closed triple and budesonide/formoterol, respectively, was 5.4% and 5.7% up to 24 weeks, and 10.0% and 12.7% up to 52 weeks. Up to 24 weeks, the incidence of pneumonia was 1.0% in the closed triple arm and 0.3% in the budesonide/formoterol arm. Up to 52 weeks, it was 1.9% in the closed triple arm and 1.8% in the budesonide/formoterol arm.

Dave Allen, Head of Respiratory R&D at GSK, commented, “Exacerbations are a major cause of morbidity in COPD and reducing these symptomatic and potentially life-threatening episodes is a priority for physicians. To observe such significant reductions in exacerbations with closed triple therapy versus budesonide/formoterol is encouraging and supports our belief that a convenient, once-daily triple therapy dosing option delivered via a single inhaler could provide compelling and clinically important treatment benefits in this more severe patient population.”

Mike Aguiar, CEO of Innoviva, Inc, added, “The results of the FULFIL study confirm that the closed triple therapy of FF/UMEC/VI is superior to dual therapy of budesonide/formoterol on the key measures of lung function, quality of life and exacerbation reduction. These results contribute to the medicine’s positive benefit/risk profile and increase understanding of the clinical value of triple therapy in those patients that physicians decide would benefit from triple therapy versus dual therapy alone.”

GSK’s plans are on schedule for regulatory submissions of the closed triple combination therapy for COPD in the US and Europe by the end of 2016.

The closed triple therapy is a combination of three medicines: fluticasone furoate (FF), an inhaled corticosteroid (ICS), umeclidinium (UMEC), a long-acting muscarinic antagonist (LAMA) and vilanterol (VI), a long-acting beta2-adrenergic agonist (LABA) delivered once-daily in GSK’s Ellipta inhaler. The FULFIL study compared FF/UMEC/VI with budesonide and formoterol, an ICS/LABA combination delivered twice-daily in the Turbohaler dry powder inhaler.

FULFIL (Lung FUnction and quality of LiFe assessment in COPD with closed trIpLe therapy) was a randomised, double-blind, double-dummy, parallel group multicentre study evaluating once-daily FF/UMEC/VI (100mcg/62.5mcg/ 25mcg) inhalation powder versus twice-daily budesonide/formoterol (400mcg/12mcg) via the Turbohaler dry powder inhaler. In the study, 1,810 patients were treated across 162 study centres globally (911 on FF/UMEC/VI and 899 on budesonide/formoterol). The population included symptomatic COPD patients (COPD assessment test = 10) with either an FEV1 of less than 50% predicted, or FEV1 of 50% to less than 80% of predicted and two moderate or one severe exacerbation in the prior year.

The co-primary endpoints were: change from baseline in trough FEV1 and SGRQ total score after 24 weeks of treatment. Other endpoints included the effect of FF/UMEC/VI on the annual rate of moderate/severe exacerbations compared with budesonide/formoterol, and the safety profile of FF/UMEC/VI compared with budesonide/formoterol over 24 weeks and 52 weeks of treatment. To provide additional longer term safety data, a sub-set of 430 patients remained on blinded study treatment for up to a total of 52 weeks.

In addition to FULFIL, the IMPACT (InforMing the PAthway of COPD Treatment) study, which began in 2014 and is expected to complete in 2017, is investigating whether FF/UMEC/VI can reduce the rate of exacerbations compared with two, once-daily dual therapies from GSK’s existing portfolio: Relvar/Breo (FF/VI), an ICS/LABA combination, and Anoro (UMEC/VI), a LAMA/LABA combination.

The closed triple combination of FF/UMEC/VI is not approved for use anywhere in the world.

COPD is a disease of the lungs that includes chronic bronchitis, emphysema or both. COPD is characterised by obstruction to airflow that interferes with normal breathing. COPD is thought to affect 329 million people worldwide.

Long-term exposure to lung irritants that damage the lungs and the airways are usually the cause of COPD. Cigarette smoke, breathing in second hand smoke, air pollution, chemical fumes or dust from the environment or workplace can all contribute to COPD. Most people who have COPD are at least 40 years old when symptoms begin.