Pharmacology Update

Fluticasone Furoate and Vilanterol Trifenatate Inhalation Powder (Breo™ Ellipta™)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD, Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationships relevant to this field of study.

A new combination of an inhaled corticosteriod and a long-acting beta2-adrenergic agonist has been approved for the treatment of chronic obstructive pulmonary disease (COPD). This once-daily fixed combination is comprised of the furoate form of fluticasone and a new long-acting beta2-adrenergic agonist, vilanterol. The product is developed in collaboration with Theravance and is marketed by GlaxoSmithKline as Breo Ellipta. Breo is the trademark for the drugs and Ellipta for the device.

Indications

Fluticasone furoate (FF) and vilanterol (VI) is indicated for long-term maintenance treatment for airflow obstruction and for reducing exacerbations in patients with COPD.1

Dosage

The maintenance dose is two blister strips of powder inhaled once daily. One strip contains 100 mcg of FF and the other 25 mcg of VI.

Potential Advantages

FF is reported to have longer lung retention time compared to fluticasone propionate.2 This allows for once-daily dosing compared to currently marketed preparations for COPD (fluticasone/salmeterol and budesonide/ formoterol) that are dosed twice daily.

Potential Disadvantages

Lactose monohydrate is an inactive ingredient and contains milk protein. The product is contraindicated in patients with severe hypersensitivity to milk protein.1

Comments

FF prolongs absorption from the lung into the systemic circulation compared to fluticasone propionate.2 Vilanterol has similar functional selectivity to salmeterol with activity for 24 hours.1,3 The efficacy of the combination of FF/VI was mainly established in four confirmatory studies, two based on pulmonary function and two based on reduction of exacerbations. Pulmonary function studies were randomized, double-blind, placebo-controlled, 24-week studies in patients with COPD (n = 2254).1,3,4 Each study compared two strengths of FF/VI (100/25 mcg and 50/25 mcg in one study, 100/25 mcg and 200/25 mcg in the other) to individual components, and placebo. Subjects had a mean age of 62, average smoking history of 44 pack years, postbronchodilator percent of predicted FEV1 of 48%, and FEV1/FVC ratio of 47%. Coprimary efficacy endpoints were weighted mean FEV1 (0-4 h) post dose on day 168 and trough FEV1 (23-24 h post dose on day 169). Difference in mean changes from baseline in weighted mean FEV1 for the 100/25 mcg dose compared to placebo was 173 mL (95% CI, 123-224) in the first study and 214 mL (95% CI, 161-266) in the second study. Differences in trough FEV1 were 115 mL and 144 mL, respectively. Improvement in measured endpoints with FF/VI was statistically significant compared to placebo in the first study and numerically improved in the second.6 VI was statistically significant to placebo in both studies. FF/VI was statistically better than FF 100 in one study and FF/ VI was not significantly better than VI 25. There were no clear benefits with the 200/25 strength compared to the 100/25 strength. The median time to onset of effect (100 mL increase in FEV1 from baseline) was 16 minutes.1 Two randomized, double-blind, 52-week studies evaluated the effect of FF/VI on annual rates of moderate/severe exacerbation (n = 3255).1 Subjects had a mean age of 64, average smoking history of 46 pack years, mean postbronchodilator percent predicted FEV1 of 45%, and mean postbronchodilator FEV1/FVC ratio of 46%. Three strengths of FF/VI were compared to VI alone. The mean annual exacerbation rates ranged from 0.70 to 1.14. FF/ VI showed statistical or numeric reduction over VI in terms of moderate-to-severe exacerbations by one-fourth to one-third of an event per year. Moderate exacerbation is worsening of symptoms that required an oral steroid and/or antibiotics. Severe exacerbation required inpatient hospitalization. In two active comparator studies, FF/VI appears to be at least as effective as fluticasone propionate/salmeterol 250/50 mcg in terms of improvement in FEV1 from baseline at day 84.6 The most frequently reported adverse events were nasopharyngitis, upper respiratory tract infection, headache, and oral candidiasis.1

Clinical Implications

FF/VI is the first once-daily fixed-combination of a corticosteroid and a long-acting beta-adrenergic agonist for the treatment of COPD. These combinations along with long-acting anticholergic agents are first-choice therapy for COPD patients with high risk of airflow limitation and exacerbation.7 An event-driven trial, the Study to Understand Mortality and Morbidity in COPD, is planned to compare FF/VI 100/25 mcg, FF 100 mcg, VI 25 mcg, and placebo with mortality as the primary endpoint.8 FF/VI is currently being evaluated for the treatment of asthma. The cost was not available at the time of this review, as the product is expected to be available during the third quarter of this year.

References

1. Breo Ellipta prescribing information. Research Triangle Park, NC: GlaxoSmithKline; May 2013.

2. Allen A, et al. Clin Pharmacokinet 2013;52:37-42.

3. Kempsford R, et al. Pulm Pharmacol Ther 2013;26:256-264.

4. Kerwin EM, et al. Respir Med 2013;107:560-569.

5. Martinez FJ, et al. Respir Med 2013;107:550-559.

6. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/UCM348806.pdf. Accessed May 22, 2013.

7. http://www.goldcopd.org/uploads/users/files/GOLD_Pocket_2013_Mar27.pdf. Accessed May 23, 2013.

8. Vestbo J, et al. Eur Respir J 2013;41:1017-1022.