T ÉCNICAS Y / O PROCEDIMIENTOS

2.1 Product Information

The proposed drug product is a fixed-dose, combination ICS/LABA dry powder administered by a novel dry powder inhaler. The combination contains fluticasone furoate (FF) as the ICS and vilanterol (VI) as the LABA in 2 double foil blister packs.

Within the foil packs, one strip contains 100 mcg of FF and the second 25 mcg of VI. A single FF/VI dose is proposed: 100/25 mcg administered as 1 inhalation once daily. The proposed trade name is Breo Ellipta®.

The sponsor proposes two indications for this new drug product, both of which are currently approved indications for other ICS/LABA products in this patient population.

 “BREO ELLIPTA is a combination inhaled corticosteroid/long-acting beta2 adrenergic agonist (ICS/LABA) indicated for long-term once-daily maintenance treatment of airflow obstruction and for reducing exacerbations in patients with chronic obstructive pulmonary disease (COPD).”

2.2 Tables of Currently Available Treatments for Proposed Indications

Table 1: Approved Treatment of Airflow Obstruction in COPD

Class Generic Name Brand Name

Albuterol sulfate Accuneb, ProAir HFA, Proventil HFA,

Ventolin HFA Levalbuterol tartrate Xopenex HFA

Pirbuterol Maxair autoinhaler

Short-acting (SABA)*

Terbutaline sulfate

Salmeterol Serevent Diskus

Formoterol Foradil Aerolizer

Arformoterol Brovana Beta2-adrenergic

agonist

Long-acting (LABA)

Formoterol Solution Perforomist

Class Generic Name Brand Name Indacaterol maleate Arcapta Neohaler Anti-cholinergic Short-acting Ipratropium bromide Atrovent HFA

Tiotropium bromide Spiriva Handihaler Long-acting

Aclidinium bromide Tudorza Pressair Combination SABA/anti-cholinergic Albuterol/Ipratropium

Albuterol/Ipratropium Combivent

Combivent respimat Fluticasone/Salmeterol Advair Diskus Corticosteroid/LABA

Budesonide/Formoterol Symbicort

Xanthine Theophylline Multiple

Table 2: Approved Treatments for Exacerbation Reduction in COPD

Class Generic Name Brand Name

Combination Corticosteroid/LABA Fluticasone/Salmeterol Advair Diskus Phosphodiesterase Inhibitors PDE4 Inhibitor Roflumilast Daliresp

2.3 Availability of Proposed Active Ingredient in the United States

Neither fluticasone furoate nor vilanterol are approved as orally-inhaled products. While vilanterol is a new molecular entity, fluticasone furoate is approved in an intranasal formulation as Veramyst Nasal Spray at a dose of 110 mcg once daily for patients ≥ 12 years of age and 55mcg once daily for children 2 to 11 years of age. It is approved for the treatment of seasonal and perennial allergic rhinitis¹.

2.4 Important Safety Issues With Consideration to Related Drugs Previous ICS/LABA development programs in COPD have identified a risk of pneumonia related to the ICS component in a dose-dependant manner.

LABA monotherapy is associated with serious asthma-related adverse events, including death and an increased risk of hospitalization. However, this risk is believed to be restricted to the asthma population and has not been demonstrated in COPD.

Additional risks highlighted in current ICS/LABA product labeling include:

 Localized infections

 Immunosupression

 Hypercorticism and adrenal suppression

 Increased systemic corticosteroid and cardiovascular effects with co-administration with strong cytochrome P450 3A4 inhibitors

 Decreases in bone mineral density

 Glaucoma and cataracts

1 Veramyst (fluticasone furoate) nasal spray; NDA 022-051 approved April 27, 2007.

 Cautious use in patients with cardiovascular or central nervous system disorders due to beta-adrenergic stimulation

2.5 Other Relevant Background Information

The table below provides a timeline of regulatory interactions with GSK regarding FF/VI and outlines the major discussion points relevant to the COPD program. In addition, discussion highlights pertinent to the COPD indication from the GSK’s interactions with the Agency for its asthma program are also highlighted.

Table 3: Milestone Interactions between the Agency and the Applicant

Date Interaction Highlights as they pertain to the COPD indication January 31,

2007 Pre-IND

(VI)  Characterize VI monocomponents prior to developing FF/VI April 29, 2008 Pre-IND  Obtain dose regimen and ranging information for VI in COPD

 Asthma data may not apply to COPD, each monocomponent must be examined in addition to the combination product

 Compare once-daily regimen to twice daily regimen May 23, 2008 IND  Safe to proceed

March 31,

2009 EOP2:

asthma  Division noted need to directly compare QD to BID regimens to establish the appropriate dosing frequency

June 17, 2009 EOP2:

COPD  GSK Identified VI 25 mcg as dose to carry into phase 3 trials, FDA could not confirm at the time based on the available data

 FDA agreed that QD and BID FF dosing regimens produced similar efficacy results and that FF 50, 100, and 200 mcg were reasonable doses to pursue in phase 3 COPD program

 Phase 3 trial design options discussed; Division noted that replicate trials were expected to support a bronchodilator claim and an exacerbation claim

December 9,

2009 Type C

meeting:

COPD mortality

 Bronchodilator dose selection in COPD should be informed by bronchodilator-sensitive population

 Discussion of mortality trial design March 24,

2010 Type C

meeting:

asthma dose selection

 once daily VI dosing appeared reasonable (HZA113310), with caveat that 12.5 mcg BID was not compared to 25 mcg QD and results from shorter phase trial may not be predictive of a longer phase 3 trial

 FDA agreed that 25 mcg VI appeared reasonable for COPD (B2C111045), but that lower doses may be efficacious for asthma June 8, 2010 Type C

meeting:

asthma

 Dose selection in COPD should be informed by bronchodilator sensitive population

Date Interaction Highlights as they pertain to the COPD indication phase 3

asthma  Bronchodilator dose may differ between asthma and COPD

 Asthma safety data should be submitted with COPD NDA to support FF/VI safety in COPD

July 13, 2011 COPD

Pre-NDA  Division noted a lack of consistent benefit of FF/VI over VI alone for spirometry data

October 12,

2012 Asthma

Pre-NDA  Division requested that asthma application be submitted concurrently with COPD application

EOP2 = end of phase 2, IND = investigational new drug, NDA = new drug application