UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, DC  20549

FORM 8-K

Current Report Pursuant

to Section 13 or 15(d) of the

Securities Exchange Act of 1934

Date of Report (Date of earliest event Reported):  September 19, 2010

THERAVANCE, INC.

(Exact Name of Registrant as Specified in its Charter)

901 Gateway Boulevard
South San Francisco, California 94080
(650) 808-6000

(Addresses, including zip code, and telephone numbers, including area code, of principal executive offices)

Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions (see General Instruction A.2. below):

o            Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)

o            Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)

o            Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))

o            Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))

Item 8.01 Other Events.

On September 19, 2010, at the European Respiratory Society Annual Congress in Barcelona, Spain, GlaxoSmithKline (GSK) presented six posters on the components of RELOVAIR™, fluticasone furoate (FF), the inhaled corticosteroid (ICS), and vilanterol trifenatate (VI), the long-acting beta2 agonist (LABA). These posters contained information from a Phase 2 study of FF, and Phase 2b studies with the individual components, FF and VI.  RELOVAIR™ is a once-daily combination medicine of FF and VI under development for the treatment of patients with chronic obstructive pulmonary disease (COPD) or asthma under the LABA collaboration between GSK and Theravance, Inc.  The six posters are attached hereto as Exhibits 99.1 to 99.6 and are incorporated herein by reference.

Item 9.01 Financial Statements and Exhibits.

(d)      Exhibits

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SIGNATURE

Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.

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EXHIBIT INDEX

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Exhibit 99.1

Woodcock A(1), Bleecker ER(2), Bateman ED(3), Busse W(4), Lötvall J(5), Snowise N(6), Forth R(7), Jacques L(6), Haumann B(6)

(1)School of Translational Medicine, University Hospital of Manchester, Manchester, UK; (2)Translational Sciences, Wake Forest University Health Sciences Winston-Salem, USA (3)Department of Medicine, University of Cape Town, Cape Town, South Africa; (4)Department of Medicine, University of Wisconsin, Madison, USA; (5)Krefting Research Centre, Gothenburg, Sweden (6)Respiratory Medicine Development Centre, GlaxoSmithKline, Uxbridge, UK; (7)Respiratory Medicine Development Center, GlaxoSmithKline, North Carolina, USA

ABSTRACT

Introduction: FF (GW685698X) is a novel ICS still active at 24h and under development as an once-daily treatment.

Objectives: To evaluate the efficacy and safety of once- and twice-daily dosing and of morning (AM) and evening (PM) dosing of FF in asthma patients >12 years.

Methods: Multicentre, randomised, double-blind, parallel group, placebo-controlled study to evaluate FF 200mcg twice daily, FF 200mcg and 400mcg once daily in the morning and FF 200mcg and 400mcg once daily in the evening compared with placebo. 652 patients were randomised to 8 weeks of treatment, with a mean age of 45 years, 65% female, baseline mean pre-bronchodilator forced expiratory volume in 1 second (FEV1) mean 67% predicted and 29% mean FEV1 reversibility. The primary endpoint was the mean change from baseline at Week 8 in trough (AM or PM) FEV1.

Results: FF 400mcg once daily in the evening and FF 200mcg twice daily resulted in comparable, placebo-adjusted improvements in PM trough FEV1 after 8 weeks of dosing (240mL and 235mL, respectively). FF 200mcg twice daily resulted in greater improvements in placebo-adjusted AM trough FEV1 than FF 400mcg once daily in the morning after 8 weeks of dosing (315mL and 202mL, respectively). FF was well tolerated in this study with a low incidence of adverse events (AEs), comparable across treatment groups. Urinary cortisol was comparable with placebo for all groups.

Conclusion: Efficacy of FF 400mcg once daily in the evening was comparable with 200mcg twice daily supporting FF as a well tolerated and efficacious once-daily ICS.

INTRODUCTION

·                  ICS are considered the most effective anti-inflammatory treatment for all severities of persistent asthma. Most current ICS formulations for asthma are indicated for twice-daily dosing; however, once-daily treatments offer the advantage of increased convenience with the subsequent potential for improved adherence and asthma control.(1)

·                  FF is a novel ICS, still active 24h after dosing,(2) which is under development for use as the ICS component of a new once-daily ICS/long-acting beta2 agonist combination for treatment of asthma and chronic obstructive pulmonary disease.

OBJECTIVES

·                  To assess the efficacy and tolerability of FF administered using a DISKUSTM/ACCUHALERTM once daily in the morning and evening, or twice daily, in asthma patients aged >12 years and symptomatic on low-dose ICS therapy.

PATIENTS AND METHODS

Study design

·                  This phase IIa, randomised, double-blind, placebo-controlled, parallel group study was conducted at 70 centres in 16 countries around the world.

·                  Patients were randomised to one of six treatments for 8 weeks (Figure 1). All treatments were administered using a DISKUSTM/ ACCUHALERTM.

·                  The study was conducted in accordance with Good Clinical Practice and the principles of the Declaration of Helsinki. Patients provided written informed consent.

Figure 1. Study design.

OD = once daily; BD = twice daily

Eligible patients

·                  Persistent asthma with use of an ICS for >3 months prior to study entry and maintained on a stable dose for 4 weeks prior to study visit 1.

·                  Baseline FEV1 50–80% of predicted normal value during visit 1 and demonstrating >12% and 200mL reversibility of FEV1 within 30min following inhalation of 200–400mcg albuterol/salbutamol aerosol (2–4 puffs) or one nebulised albuterol/salbutamol treatment at visit 1.

·                  All patients had to be able to replace SABAs with albuterol/salbutamol aerosol for use as needed during the study period and to be able to withhold all inhaled short-acting beta sympathomimetic bronchodilators for >6h prior to study visits. (Note: use of nebulised albuterol/salbutamol was not permitted during the study except at visit 1).

Endpoints

·                  The single efficacy endpoint was the mean change from baseline at Week 8 (last assessment on treatment using last observation carried forward [LOCF]) in the trough (morning or evening pre-dose and pre-rescue bronchodilator) FEV1.

·                  Safety endpoints included incidence of AEs (defined using the MedDRA dictionary), oropharyngeal examinations, haematology and clinical chemistry, urinalysis, 24h urinary cortisol excretion, vital signs and withdrawals due to worsening asthma.

RESULTS

·                  In total, 646 patients were included in the ITT population. 126 patients withdrew from the ITT population

·                  in the placebo group, 36% (n=36) of patients withdrew overall (21% lack of efficacy, 13% exacerbation and 2% other [decided to withdraw, AE, non-compliance, lost to follow-up, protocol violation, liver function test abnormality or other reason])

·                  in the FF 200mcg once-daily morning and evening groups, 19% (n=20) and 20% (n=21) of patients, respectively, withdrew overall (10% lack of efficacy, 2% exacerbation, 8% other and 13% lack of efficacy, 3% exacerbation, 5% other, respectively)   

·                  in the FF 400mcg once-daily morning and evening groups, 14% (n=15) and 15% (n=17) of patients, respectively, withdrew overall (6% lack of efficacy, 2% exacerbation, 5% other and 8% lack of efficacy, 3% exacerbation, 4% other, respectively)

·                  in the FF 200mcg twice-daily group, 15% (n=17) of patients withdrew overall (12% lack of efficacy, 0 exacerbation and 3% other).

·                  Patient baseline characteristics were similar in the six treatment groups (Table 1).

Table 1. Patient baseline characteristics (ITT population).

Efficacy (ITT population)

·                  There were statistically significant improvements in trough FEV1 with each FF treatment group compared with placebo (Figure 2, Table 2).

·                  FF 400mcg once daily dosed in the evening showed similar placebo-adjusted improvements in evening trough FEV1 at Week 8 versus FF 200mcg twice daily (240mL vs 235mL).

Figure 2. Adjusted treatment difference in trough FEV1 (L) (LOCF; ITT population).

CI = confidence interval

Table 2. Change from baseline in trough FEV1 (L) (LOCF) at Week 8, by PM versus AM FEV1 and treatment group (ITT population).

LSM = least square mean; SE = standard error

·                  FF 400mcg once daily dosed in the morning produced a smaller improvement in placebo-adjusted trough morning FEV1 at Week 8 than FF 200mcg twice daily (202mL vs 315mL).

·                  A >200mL increase in trough FEV1 versus placebo was seen with FF 400mcg once daily dosed morning or evening and with FF 200mcg twice daily, but not with the two FF 200mcg once-daily groups.

·                  Week 8 morning and evening FEV1 responses for each treatment group are shown in Figure 3.

Figure 3. Comparison of AM and PM FEV1 at Week 8 following once-daily dosing in the PM or AM, or twice-daily dosing (ITT population).

Safety

·                  FF treatment was well tolerated, with a similar incidence of on-treatment AEs in the placebo (28%) and FF treatment groups (31–39%).

·                  The most common AEs are listed in Table 3. The frequency of AEs did not appear to be related to FF dose.

·                  Of four serious AEs reported (two during and two post-treatment), only one case of angioedema in the FF 200mcg once-daily morning group was considered to be possibly related to study treatment; the three other serious AEs were recurrent paroxysm of atrial fibrillation (FF 400mcg once-daily morning group), and cerebrovascular accident and spontaneous abortion (both FF 200mcg twice-daily group). Eleven patients withdrew due to AEs (three on FF 200mcg once-daily morning dosing, one on 200mcg once-daily evening, three on 400mcg once-daily morning, three on 400mcg once-daily morning and one on FF 200mcg twice-daily).

·                  There were no safety concerns with regard to vital signs, oropharyngeal examinations, or laboratory parameters. Oral candidiasis (coded as oral candidiasis, oropharyngeal candidiasis or candidiasis) occurred at an incidence of 0–4% across all treatment arms.

·                  The incidence of asthma exacerbations was low with FF treatment (<1–4% vs 14% for placebo).

·                  24h urinary cortisol excretion ratios (Week 8/baseline) were similar for all FF treatment groups (range 0.78–1.03) and placebo (0.87), between morning and evening dosing, and between once- and twice-daily dosing.

Table 3. Most common on-treatment AEs (>3% incidence in any treatment group; ITT population).

CONCLUSIONS

·                  Once-daily treatment with FF 400mcg dosed in the evening or morning showed clinically and statistically significant improvements in trough FEV1 (>200mL).

·                  FF 400mcg administered in the morning provided a smaller improvement in efficacy compared with FF 200mcg twice daily.

·                  FF 400mcg administered in the evening provided similar efficacy to FF 200mcg twice daily.

·                  The data support FF as an effective and well-tolerated once-daily ICS for patients with mild-to-moderate asthma.

REFERENCES

(1)          Price D, et al. BMC Pulm Med 2010;10:1.

(2)          van den Berge M, et al. Allergy 2010. Epub ahead of print.

ACKNOWLEDGEMENTS

·                  This study was sponsored by GlaxoSmithKline (ClinicalTrials.gov: NCT00398645; protocol number: FFA106783).

·                  Editorial support (in the form of writing assistance, assembling tables and figures, collating author comments, grammatical editing and referencing) was provided by Anna Ireland at Gardiner-Caldwell Communications and was funded by GlaxoSmithKline.

Exhibit 99.2

Bateman ED(1), Bleecker ER(2), Busse W(3), Lötvall J(4), Woodcock A(5), Forth R(6), Medley H(7), Jacques L(7), Haumann B(7)

(1)Department of Medicine, University of Cape Town, Cape Town, South Africa; (2)Translational Sciences, Wake Forest University Health Sciences Winston-Salem, USA (3)Department of Medicine, University of Wisconsin; Madison, USA; (4)Krefting Research Centre, Gothenburg, Sweden; (5)School of Translational Medicine, University Hospital of Manchester Manchester, UK; (6)Respiratory Medicine Development Center, GlaxoSmithKline, North Carolina, USA; (7)Respiratory Medicine Development Centre, GlaxoSmithKline, Uxbridge, UK

ABSTRACT

Introduction: FF (GW685698X) is an ICS still active at 24h, in development as a once-daily treatment in combination with the long-acting beta2 agonist (LABA), vilanterol trifenatate (VI; GW642444M) for asthma and chronic obstructive pulmonary disease (COPD).

Objectives: To compare the efficacy and safety of FF (dry powder) at four doses administered via a novel single-step activation inhaler in patients >12 years old with persistent uncontrolled asthma. Fluticasone propionate (FP) served as an active control.

Methods: In a randomised, double-blind, placebo-controlled, parallel group study, 598 patients received one of six treatments: FF (25, 50, 100 or 200mcg) once daily, FP 100mcg twice daily or placebo for 8 weeks. The primary endpoint was change from baseline in trough (pre-dose) forced expiratory volume in 1 second (FEV1) at Week 8.

Results: A dose response was observed for trough FEV1 between FF 25–200mcg once daily including and excluding placebo (linear trend analysis p<0.001 and p=0.03, respectively). At Week 8, relative to placebo FF 50–200mcg once daily had significantly greater increases in trough FEV1 from baseline (p<0.05) with FF 100mcg and 200mcg achieving a >200mL increase. Secondary endpoints peak expiratory flow (PEF), symptom-free and rescue-free 24h periods supported the efficacy of FF 50–200mcg once daily doses and FP. Overall, FF was well tolerated. The incidence of oral candidiasis was low (0–4%). 24h urinary cortisol excretion ratios (Week 8/baseline) were similar across treatments (FF 0.98–1.21 and placebo 1.04).

Conclusion: The data support the use of FF (100 and 200mcg) as a once-daily treatment in persistent uncontrolled asthma.

INTRODUCTION

·                  FF is an ICS with a pharmacological profile that demonstrates greater retention in the lung and a longer duration of action than FP.(1)

·                  FF is under development as a once-daily inhaled asthma therapy, administered in a novel dry powder inhaler (DPI) formulation in combination with VI, a new LABA with 24h activity.(2)

OBJECTIVE

·                  To compare the efficacy and safety of FF (dry powder) versus placebo at four doses administered via a novel single-step activation inhaler in patients >12 years old with persistent uncontrolled asthma. FP served as an active control.

PATIENTS AND METHODS

Study design

·                  A phase IIb, randomised, double-blind, double-dummy, parallel-group, placebo- and active-controlled study conducted at 142 centres in 14 countries.

·                  Eligible patients had: persistent asthma (defined by the National Institutes of Health criteria)(3) and were symptomatic on short-acting beta2 agonists (SABAs) or other non-steroid agents; FEV1 (% of predicted normal) 40–90% (evening; PM) or 40–85% (morning; AM); reversibility of FEV1 of >12% and >200mL with albuterol/salbutamol aerosol inhaler. All patients had to be able to replace their current SABAs with albuterol/salbutamol aerosol for use as needed during the study period.

·                  After 4-weeks run-in (on usual medications), patients entered the treatment period if they were symptomatic (combined daily asthma symptom score >1 or albuterol/ salbutamol use on >4 of the last 7 days of run-in) and their evening pre-dose FEV1 was 40–90% of predicted normal.

·                  Eligible patients were randomised to one of six treatment groups for 8 weeks using a double dummy design (Figure 1): one of four doses of FF (25–200mcg once daily PM using a novel single-step DPI; these patients also took placebo twice daily via DiskusTM/AccuhalerTM); FP (twice daily via DiskusTM/AccuhalerTM; these patients also took placebo once daily via the novel DPI); or placebo (every evening via the novel DPI and twice daily via DiskusTM/AccuhalerTM). Patients were assessed at 1, 2, 4, 6 and 8 weeks during treatment.

Endpoints

·                  Primary: the mean change from baseline in trough (pre-dose, pre-rescue bronchodilator) evening FEV1 at Week 8 in each treatment group. The main treatment comparison was to test for a linear dose response across the four FF doses.

Figure 1. Study design.

OD = once daily; BD = twice daily

·                  Secondary: mean change from baseline over the 8-week treatment period in daily trough (pre-dose, pre-rescue bronchodilator) PM PEF, daily AM PEF; % of symptom-free and rescue-free 24h periods; number of withdrawals due to lack of efficacy.

·                  Safety: incidence of adverse events (AEs) during treatment; evidence of oral candidiasis (visits 1, 3–8); haematology, clinical chemistry and urinalysis parameters before and end of study; 24h urinary cortisol excretion; vital signs (visits 1, 3–8).

RESULTS

·                  Of 601 patients randomised, 598 received at least one dose of study treatment (intent-to-treat [ITT] population). The demographics and baseline characteristics were similar across groups (Table 1): the patients’ mean age was 37–41 years; over half of them had a >10-year history of asthma, and around 20% had suffered an exacerbation during the last 6 months.

Table 1. Demographics and baseline characteristics (ITT population).

Efficacy (ITT population)

·                  At Week 8, all active treatment groups showed a >200mL improvement in trough FEV1 from baseline; the FF 100mcg and 200mcg doses achieved a >200mL difference compared with placebo (p<0.001). FF 50mcg was also significantly better than placebo (129mL; p<0.05). A difference of 101mL was achieved with FF 25mcg, but this was not significantly better than placebo (p=0.095; Figure 2).

·                  There was a significant dose-response relationship for the baseline–Week 8 change in trough PM FEV1 across FF dose groups (25–200mcg), both with placebo (p<0.001) and without (p=0.03).

·                  Both AM and PM PEF values (Figure 3) were increased from baseline at Week 8 in all FF treatment groups. There were significantly greater improvements in PEF values versus placebo in all active treatment groups (p=0.041 to p<0.001).

Figure 2. Adjusted treatment differences of change from baseline in trough FEV1 (LOCF) at Week 8 (ITT population).

Note: analysis performed using analysis of covariance (ANCOVA) with covariates of baseline, country, sex, age and treatment

Figure 3. Change from baseline in PM and AM PEF over Weeks 1–8 (ITT population).

·                  The percentage of symptom-free 24h periods over Weeks 1–8 was significantly higher versus placebo for all treatment groups (p<0.005) except the FF 25mcg group (p=0.128); similarly, the percentage of rescue-free 24h periods over Weeks 1–8 was significantly higher versus placebo for all treatment groups (p<0.031) except the FF 25mcg group (p=0.110) (Figure 4).

·                  Withdrawal rates due to lack of efficacy were 15% and 11% for placebo and FP, respectively, and ranged from 3–9% for FF dose groups; there was a statistically significant difference for lower withdrawal rates due to lack of efficacy with the 50mcg (p=0.004) and 100mcg (p=0.032) FF dose groups versus placebo (Figure 5).

SAFETY

·                  FF therapy was generally well tolerated (Table 2). The most common AEs were headache, oropharyngeal pain and nasopharyngitis (Table 2). There was no evidence of a relationship between FF dose and the incidence of any of the most common AEs.

·                  Incidence of candidiasis was low (0–4%), but occurred at a higher incidence in the 50mcg (4%) and 100mcg (3%) FF once-daily PM dose groups.

Figure 4. Symptom-free and rescue-free 24h periods over Weeks 1–8.

Figure 5. Treatment discontinuation due to lack of efficacy (cumulative incidence).

Note: patients are represented from their date of randomisation to their date of withdrawal due to lack of efficacy

·                  None of the six on-treatment serious AEs reported by four patients (snake bite [FF 25mcg], depression [FF 100mcg], gastritis, chest pain, hyperhidrosis, hypertension [all FP]) were considered to be study drug-related and there were no deaths or hospitalisations associated with AEs.

·                  There were no statistically significant differences in urinary cortisol excretion between placebo and any of the FF groups or FP (Figure 6) and no events attributable to systemic corticosteroid effects were reported. No clinically important changes in laboratory parameters or vital signs were recorded.

Table 2. Summary of AEs and most common on-treatment AEs (>3% incidence in any treatment group; ITT population).*

*Oral candidiasis was diagnosed in 1 (1%), 1 (<1%) and 2 (2%) of patients in the FF 50, 100 and 200mcg OD arms, respectively when coded as ‘oropharyngeal candidiasis’, and in 1 (<1%) patients in the FP 100mcg BD arm. It was diagnosed in 1 (1%) and 2 (2%) of patients in the FF 50 and 100mcg OD arms, respectively when coded as ‘candidiasis’, and in 2 (2%) patients in the FF 50mcg OD arm when coded as ‘oral candidiasis’

Figure 6. Adjusted treatment ratios for 24h urinary cortisol excretion (urinary cortisol population).*

Note: analysis performed using ANCOVA with covariates of country, sex, age, treatment and the log of the baseline values; *The urinary cortisol population consisted of 425 (71%) patients in the ITT population who had urine samples with no factors that would confound the analysis of urinary cortisol

CONCLUSIONS

·                  A dose-response was observed for trough FEV1 between FF 25–200mcg once daily, including (p<0.001) and excluding (p=0.03) placebo; at Week 8 the 50–200mcg FF doses were all significantly better than placebo with the 100 and 200mcg FF doses resulting in a >200mL difference in FEV1 from baseline compared with placebo.

·                  Secondary endpoints, including PM and AM PEF and symptom-free and rescue-free 24h periods, further supported the efficacy of FF 50–200mg once-daily doses.

·                  The incidence of on-treatment AEs was low across the treatment groups and there was no evidence of FF dose impacting on incidence of AEs. 24h urinary cortisol excretion ratios (Week 8/baseline) were similar across treatment groups.

·                  FF 50–200mcg given once daily in the evening provided effective asthma control and was well tolerated in patients symptomatic on non-steroid asthma therapy. The data support the 100mcg FF once-daily dose as the optimal dose for further evaluation in phase III studies.

REFERENCES

(1)          Salter M, et al. Am J Physiol Lung Cell Mol Physiol 2007;293:L660–67.

(2)          Cazzola M, et al. Eur Respir J 2009;34:757–69.

(3)          National Institutes of Health (NIH) 2007. NIH Publication No. 07-4051.

ACKNOWLEDGEMENTS

·                  This study was sponsored by GlaxoSmithKline (ClinicalTrials.gov: NCT00603382; protocol number FFA109687).

·                  Editorial support (in the form of writing assistance, assembling tables and figures, collating author comments, grammatical editing and referencing) was provided by Anna Ireland at Gardiner-Caldwell Communications and was funded by GlaxoSmithKline.

Exhibit 99.3

Bleecker ER(1), Bateman ED(2), Busse W(3), Lötvall J(4), Woodcock A(5), Tomkins S(6), House KW(7), Jacques L(6), Haumann B(6)

(1)Translational Sciences, Wake Forest University Health Sciences Winston-Salem, USA; (2)Department of Medicine, University of Cape Town, Cape Town, South Africa (3)Department of Medicine, University of Wisconsin, Madison, USA; (4)Krefting Research Centre, Gothenburg, Sweden; (5)School of Translational Medicine, University Hospital of Manchester, Manchester, UK (6)Respiratory Medicine Development Centre, GlaxoSmithKline, Uxbridge, UK; (7)Respiratory Medicine Development Centre, GlaxoSmithKline, North Carolina, USA

ABSTRACT

Introduction: FF (GW685698X) is a novel ICS still active at 24h and under development as a once-daily treatment in combination with the long-acting beta2 agonist (LABA) vilanterol trifenatate (GW642444M) for asthma and chronic obstructive pulmonary disease (COPD).

Objectives: To compare the relative efficacy and safety of four doses of FF (dry powder), administered using a novel single-step activation inhaler in patients >12 years with moderate asthma uncontrolled on low doses of ICS (fluticasone propionate [FP] 200mcg/day or equivalent). FP was used as an active control.

Methods: This randomised, double-blind, double-dummy, placebo-controlled, parallel group study, randomised 622 patients to one of six treatments: FF (100, 200, 300 or 400mcg) once daily, FP 250mcg twice daily or placebo for 8 weeks. The primary endpoint was change in 24h trough (pre-dose) forced expiratory volume in 1 second (FEV1) from baseline at Week 8.

Results: Primary: at Week 8 relative to placebo, all doses of FF and FP demonstrated significantly greater increases from baseline in trough FEV1 (p<0.001) and >200mL increase. There was no evidence of a dose response between FF doses. Secondary: withdrawals due to lack of efficacy were low, and peak expiratory flow (PEF) results supported the efficacy of FF 100–400mcg and FP. Oral candidiasis was low (0–4%) and the range of 24h urinary cortisol excretion ratios (Week 8/baseline) was similar across treatments, including placebo.

Conclusion: This dose-ranging study supports the use of FF as once-daily treatment for patients with asthma uncontrolled on low ICS doses.

INTRODUCTION

·                  ICS are the most effective anti-inflammatory medications currently available for long-term control of all severities of persistent asthma.(1)–(3)

·                  Most current inhaled steroids are more effective when taken twice daily rather than once daily.(3)

·                  Patients not controlled on low-dose ICS may require combination therapy with a LABA or twice-daily therapy with a higher dose of ICS.(1)–(3)

·                  FF is a novel ICS, still active 24h after dosing, which is under development for use as the ICS component of a new once-daily ICS/LABA combination for asthma and COPD.

OBJECTIVE

·                  To evaluate the dose response, efficacy and safety of four dose regimens of FF administered once daily in the evening in patients aged >12 years with persistent asthma uncontrolled on low-dose ICS therapy, in order to identify the appropriate dose of FF for further investigation.

METHODS

·                  Phase IIb, multicentre, randomised, double-blind, double-dummy, parallel-group, placebo-controlled study, involving nine clinic visits (Figure 1).

·                  Eligible patients had an FEV1 of 40–90% (for PM visit) or 40–85% (for AM visit) of the predicted normal value at visit 1 and demonstrated a >12% and >200mL reversibility of FEV1 within ~30min following four inhalations of albuterol/salbutermol inhalation aerosol. Patients had been using an inhaled ICS for >8 weeks prior to visit 1 and were able to replace their current short-acting beta2 agonist with albuterol/salbutamol at visit 1 for use during the study.

·                  FF once daily was administered in the evening via a novel dry powder inhaler given at doses of 100, 200, 300 and 400mcg versus placebo.

·                  FP 250mcg twice daily was administered via DISKUS™/ACCUHALER™ inhaler and was included for assay sensitivity and compared against placebo for the relative magnitude of response with FF doses investigated.

Efficacy and safety measures methods

·                  Primary efficacy endpoint: mean change from baseline in trough (PM pre-dose and pre-rescue bronchodilator) FEV1 at the end of the 8-week treatment period.

Figure 1. Study design.

OD = once daily; BD = twice daily

·                  Secondary efficacy endpoints: mean change from baseline in daily trough (pre-dose and pre-rescue bronchodilator) PM PEF and daily AM PEF averaged over the treatment period; mean change from baseline in the percentage of symptom-free 24h periods and rescue-free 24h periods during the treatment period; and number of withdrawals due to lack of efficacy during the treatment period.

·                  Safety assessments included: incidence of adverse events (AEs); incidence of oral candidiasis at clinic visits 1 and 3–8; urinary cortisol excretion; and laboratory tests and vital signs, before and at the end of the 8-week treatment period.

RESULTS

Efficacy study design

·                  Patient characteristics were comparable across the groups (Table 1).

Table 1. Demographic and baseline clinical characteristics (ITT population).

ITT = intent-to-treat

·                  All dosages of FF demonstrated significant (p<0.001) mean increases in FEV1 from baseline compared with placebo (Figure 2).

·                  There was no evidence of a dose response for the four FF groups.

Figure 2. Adjusted treatment differences of change from baseline in trough FEV1 (LOCF) at Week 8 (ITT population).

Note: analysis performed using an analysis of covariance (ANCOVA) with covariates of baseline, country, sex, age and treatment

·                  The results of a test of linear trend in dose response, excluding placebo group showed no significant relationship between response and dose of FF (p>0.05; 95% CI: –0.060 to 0.616). The estimate of the slope was 0.278mL/mcg. The results of the test for linear trend in dose response, including placebo were significant (p<0.001; 95% CI: 0.391 to 0.900). The estimate of the slope was 0.646mL/mcg.

·                  FF once daily PM and FP twice daily produced significantly different (improved) changes relative to placebo in daily trough (pre-dose and pre-rescue bronchodilator) PM PEF and daily AM PEF (p=0.018 to p<0.001; Figure 3).

Figure 3. PEF over Weeks 1–8
a) PM and b) AM.

·                  The change in percentage of symptom-free 24h periods were significantly different from placebo for FF 400mcg once daily PM (p=0.010) and FP 250mcg twice daily (p=0.002), but not for FF 100, 200 and 300mcg once daily PM (p=0.311, p=0.592 and p=0.097, respectively; Figure 4a). The change in percentage of rescue-free 24h periods were significantly different from placebo for FF 100, 300 and 400mcg once daily PM, and FP 250mcg twice daily (p=0.030, p=0.031, p=0.045 and p<0.001, respectively) but not for FF 200mcg once daily (p=0.06; Figure 4b).

·                  Significantly higher withdrawals due to lack of efficacy were observed with placebo (33%) compared with the active treatment groups (p<0.001 for all FF doses and p=0.002 for FP; Figure 5).

Figure 4. Symptom-free and rescue-free 24h periods over Weeks 1–8.

Figure 5. Treatment discontinuation due to lack of efficacy (cumulative incidence).

Note: patients are represented from their date of randomisation to their date of withdrawal due to lack of efficacy

Safety

·                  Overall, FF was well tolerated, with no apparent dose-related increase in the frequency of the most commonly reported AEs across the four doses of FF (Table 2).

·                  Seven patients withdrew due to AEs, including one serious AE (asthma exacerbation); three of these events were considered treatment-related (pharyngitis and throat infection [both in the FF 100mcg group]; bilateral thigh pain [FF 400mcg group]).

·                  The urinary cortisol excretion ratios were not significantly different between placebo and any dose groups of FF or FP 250mcg twice daily (Figure 6).

Table 2. Most common on-treatment AEs (>3% incidence in any treatment group; ITT population).

*Two additional patients, 1 (<1%) in the FF 300mcg OD arm and 1 (1%) in the FP 250mcg BD arm were diagnosed as having oral candidiasis, coded as ‘oropharyngeal candidiasis’

·                  No treatment-related clinically important changes were apparent for the mean and median laboratory values noted at Week 1 and Week 8 for haematology and clinical chemistry analytes, or vital signs.

Figure 6. Adjusted 24h urinary cortisol excretion ratios.*

Note: analysis performed using ANCOVA with covariates of baseline, country, sex, age and treatment and the log of baseline values;

*The urinary cortisol population consisted of 417 (68%) patients in the ITT population who had urine samples with no factors that would confound the analysis of urinary cortisol

CONCLUSIONS

·                  These results support FF as an effective and well-tolerated ICS at doses ranging from 100 to 400mcg administered once daily in the evening, in patients with asthma uncontrolled on low doses of ICS.

·                  On the basis of the efficacy and safety data, FF 100mcg and 200mcg are likely to be the most effective doses for this population of asthma patients.

REFERENCES

(1)          Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention 2007. Available at: www.ginasthma.org.

(2)          National Institutes of Health (NIH). Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Full Report 2007. NIH Publication No. 07-4051. Available at: http://www.nhlbi.nih.gov.

(3)          British Thoracic Society (BTS). British Guideline on the Management of Asthma. May 2008. Available at: www.brit-thoracic.org.uk.

ACKNOWLEDGEMENTS

·                  This study was sponsored by GlaxoSmithKline (ClinicalTrials.gov: NCT00603278; protocol number FFA109685).

·                  Editorial support (in the form of writing assistance, assembling tables and figures, collating author comments, grammatical editing and referencing) was provided by Anna Ireland at Gardiner-Caldwell Communications and was funded by GlaxoSmithKline.

Exhibit 99.4

Busse W(1), Bleecker ER(2), Bateman ED(3), Lötvall J(4), Woodcock A(5), Forth R(6), Davis AM(6), Jacques L(7), Haumann B(7)

(1)Department of Medicine, University of Wisconsin, Madison, USA; (2)Translational Sciences, Wake Forest University Health Sciences Winston-Salem, USA (3)Department of Medicine, University of Cape Town, Cape Town, South Africa; (4)Krefting Research Centre, Gothenburg, Sweden; (5)School of Translational Medicine, University Hospital of Manchester Manchester, UK, (6)Respiratory Medicine Development Center, GlaxoSmithKline, North Carolina, USA; (7)Respiratory Medicine Development Centre, GlaxoSmithKline, Uxbridge, UK

UPDATED ABSTRACT

Introduction: FF (GW685698X) is a novel ICS still active at 24h, in development as a once-daily treatment in combination with the long-acting beta2 agonist (LABA) vilanterol trifenatate (VI; GW642444M) for asthma and chronic obstructive pulmonary disease.

Objectives: To evaluate the efficacy and safety of FF administered using a novel single-step activation dry powder inhaler (DPI) in patients >12 years uncontrolled on moderate doses of ICS (fluticasone propionate [FP] 500mcg/day or equivalent). FP was used as an active control.

Methods: In this randomised, double-blind, placebo-controlled, double-dummy, parallel group study, 627 patients were randomised to FF (200, 400, 600 or 800mcg) once daily, FP 500mcg twice daily or placebo for 8 weeks. Primary endpoint: change in trough (pre-dose) forced expiratory volume in 1 second (FEV1) at Week 8.

Results: Primary: the test of linear trend in FF dose response relative to placebo for trough FEV1 at Week 8 was significant (p<0.001). However, no dose response between FF doses was observed. Secondary: peak expiratory flow (PEF), symptom-free and rescue medication-free 24h periods, and withdrawals due to lack of efficacy supported the efficacy of FF 200–800mcg doses and FP. Incidence of oral candidiasis was highest for FF 800mcg (12%). 24h urinary cortisol excretion ratios (Week 8/baseline) for FF were similar to placebo except for FF 800mcg, which was significantly lower.

Conclusion: This study supports the use of FF as a once-daily treatment for patients with asthma uncontrolled on moderate ICS doses.

INTRODUCTION

·      ICS are the most effective anti-inflammatory treatment for persistent asthma(1)–(3) and play a critical role in first-line treatment.

·      There is a need for improved treatment options for patients with uncontrolled disease; most ICS are dosed twice daily, but once-daily dosing can improve treatment adherence,(4) and may improve outcomes for patients.(5),(6)

·      FF a novel ICS still active at 24h, is currently in development as the ICS component of a new ICS/LABA once daily inhaled combination treatment for asthma.

OBJECTIVE

·      Evaluate the efficacy and safety of four doses of FF dosed once daily in the evening for 8 weeks, using a novel single-step activation DPI, in patients >12 years whose symptoms were uncontrolled on moderate doses of ICS (FP 500mcg/day or equivalent).

METHODS

·      A phase IIb, randomised, double-blind, double-dummy, placebo-controlled, parallel-group, multicentre, dose-ranging study in adolescent and adult patients with persistent asthma (Figure 1).

·      Eligible patients (>12 years old) had persistent asthma,(2) with an evening pre-dose % predicted FEV1 of 40–90% of their predicted normal value, and >12% and >200mL reversibility of FEV1 following albuterol/salbutamol inhalation. They had been using an ICS for >8 weeks prior to their first visit (at a stable dose for >4 weeks).

·      All patients replaced their short-acting beta2 agonists with albuterol/salbutamol inhalation aerosol at visit 1, for use as needed during the study.

·      Following a 28-day run-in (to assess baseline asthma status, daily diary compliance, and for safety evaluations) during which patients continued their prior ICS therapy at a fixed dose, they were randomly assigned to receive

·      FF (200, 400, 600 or 800mcg once daily [evening; PM]) via novel DPI plus placebo twice daily (morning [AM] and PM) via DISKUS™/ACCUHALER™

·      FP (500mcg twice daily AM and PM) via DISKUS™/ACCUHALER™ plus placebo once daily (PM) via novel DPI

·      placebo once daily (PM) via novel DPI plus placebo twice daily (AM and PM) via DISKUS™/ACCUHALER™.

·      All medications were blinded to investigators and patients, and each patient received two devices at each visit (novel DPI and DISKUS™/ACCUHALER™).

·      Patients stopped their maintenance ICS therapy for the duration of treatment (visit 3–8), and received study medication for 56 days (8 weeks). A follow-up clinic visit or phone contact was conducted 1 week after completing treatment.

Efficacy and safety measures

·      The primary endpoint was the mean change from baseline in PM trough FEV1 (pre-dose and pre-rescue bronchodilator) at Week 8

·      the primary comparison was the test for linear dose response in FEV1 across the four doses of FF and placebo (intent-to-treat [ITT] population; analysis of covariance [ANCOVA] with last observation carried forward [LOCF]).

·      Secondary endpoints

·      mean change from baseline in daily PM trough (pre-dose and pre-rescue bronchodilator) PEF and daily AM PEF, averaged over the treatment period

·      mean change from baseline in % symptom-free and % rescue medication-free 24h periods

·      withdrawals due to lack of efficacy.

Figure 1. Study design.

OD = once daily; BD = twice daily

·      Safety assessments included

·      incidence of adverse events (AEs; categorised using the MedDRA coding dictionary, Version 11)

·      oropharyngeal examination for oral candidiasis

·      laboratory tests (haematology, clinical chemistry, urinalysis parameters [pre- and post-treatment]) and vital signs

·      24h urinary cortisol excretion (pre- and post-treatment).

RESULTS

·      627 patients were randomised to FF (200, 400, 600 or 800mcg) once daily PM, FP 500mcg twice daily or placebo for 8 weeks; 622 patients received one or more doses (the ITT population).

·      82–92% of the FF groups and 88% of the FP group completed the study, vs 63% of the placebo group (Table 1).

Table 1. Patient disposition.

·      Demographic characteristics were evenly matched between treatment groups, as were clinical characteristics and measures of pulmonary function at screening, indicating a similar severity of illness between groups (Table 2).

Table 2. Demographic and clinical characteristics

(ITT population).