GlaxoSmithKline : GSK presents data at ATS on the role of blood eosinophil levels as a potential biomarker in the treatment of COPD

Issued: London, UK

GSK today presented two abstracts at the American Thoracic Society (ATS) meeting that provide data on the role of blood eosinophils as a potential biomarker to determine responsiveness to treatment with an inhaled corticosteroid (ICS) in patients with COPD. The findings from these and other post-hoc analyses, combined with ongoing prospective studies, could provide important information regarding how a patient's blood eosinophil level influences their individual benefit/risk with an ICS containing treatment.

Based on a growing understanding of the potential role of the eosinophil, a type of white blood cell, GSK conducted a post-hoc analysis of a number of double-blind, randomised clinical trials of Seretide® 500/50μg (fluticasone propionate/salmeterol or FP/SAL) and Flixotide® 500μg (fluticasone propionate or FP)*, where blood eosinophil level data were available to allow patient outcomes to be assessed by those with a blood eosinophil level of ≥2% and

The details from each study were as follows:

1. Blood eosinophil count as a predictor of response to inhaled corticosteroids (ICS) in COPD
   (Barnes NC, Pavord ID, Jones PW, Wedzicha JA, Lettis S, Locantore N, Pascoe S)
   
   A post-hoc analysis of data from three randomised, clinical trials of at least 1-year duration comparing moderate/severe exacerbation rates in a total of 3,045 patients was conducted. Patients within each study were randomised to receive the following:
   
   - INSPIRE (SCO40036; NCT00361959): twice-daily FP/SAL 500/50μg or once-daily tiotropium 18μg in patients with severe/very severe COPD[i]
   
   - TRISTAN (SFCB3024): twice-daily FP/SAL 500/50μg versus FP 500μg or SAL 50μg or placebo in patients with moderate-to-severe COPD[ii]
   
   - SCO30002: twice-daily FP/SAL 500/50μg or placebo in patients with moderate-to-severe COPD.[iii]
   
   The results showed that patients with a baseline blood eosinophil level of ≥2% receiving FP/SAL had a reduction in exacerbation rates compared to those receiving tiotropium or placebo. This was not seen in those with blood eosinophil levels
   
   - In INSPIRE, patients with a blood eosinophil level of ≥2% who received FP/SAL had a reduction in exacerbation rates compared to those receiving tiotropium (p=0.006), however those with blood eosinophil levels
   
   - TRISTAN showed that in patients receiving FP/SAL, FP and SAL versus placebo, relatively greater reductions were observed in those with a blood eosinophil level ≥2% versus
   
   - In study SCO30002, FP/SAL and FP were associated with a lower exacerbation rate than placebo in the ≥2% eosinophils subgroup (p>0.05), but the reverse was observed in patients with blood eosinophil levels
   
   These analyses did not appear to show any clear relationship between baseline blood eosinophil levels and the incidence of pneumonia.
   
   
2. Do inhaled corticosteroids (ICSs) reduce rate of decline of lung function in COPD patients with eosinophil count≥2%
   (Barnes NC, Sharma R, Lettis S, Calverley PMA)

A post-hoc analysis was conducted on data from the ISOLDE study (FLIT78)[iv], which involved 738 patients who were randomised to receive FP 500μg twice daily or placebo. Patients were assessed over a 3-year study period to determine the effect on rate of decline in post-bronchodilator FEV1 and secondary endpoints of exacerbation rates and overall health status.

Results from this analysis showed that patients with blood eosinophil levels ≥2% receiving FP showed a slower rate of decline of lung function (p=0.003) compared to placebo, whereas a similar effect was not observed in the

A lower rate of exacerbations with FP vs placebo was observed for patients with both a baseline blood eosinophil count of > 2% (p=0.281).

The incidence of pneumonia was higher with FP versus placebo in the blood eosinophil

Darrell Baker, SVP and Head, Global Respiratory Franchise, GSK said: "In addition to developing new treatments for COPD, we are committed to improving scientific understanding of which types of patients benefit from which medicine, based on an individual's needs, but also and importantly how this is balanced by their individual risk factors. I am excited that GSK is at the forefront of such activities, which we hope may ultimately lead to an era of more personalised medicine and support the physician in selecting the right medicine for the right patient."

About COPD:
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.

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.

About eosinophils:

Eosinophils are a type of white blood cell thought to play a role in the development of allergic airway inflammation.

Although primarily associated with asthma, eosinophilic airway inflammation is present in some patients with COPD and has been shown to occur during exacerbations of COPD.[v] A blood eosinophil count of ≥2% has been suggested to identify a group of patients who show a greater response to inhaled corticosteroid treatment in COPD.[vi]

Important Safety Information for FP/SAL (Advair/Seretide)

• FP/SAL is indicated for the treatment of asthma in patients aged 4 years and older.
• Long-acting beta2-adrenergic agonists (LABA), such as salmeterol, one of the active ingredients in FP/SAL, increase the risk of asthma-related death. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients.
• Therefore, when treating patients with asthma, physicians should only prescribe FP/SAL for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue FP/SAL) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use FP/SAL for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.
• FP/SAL 250/50 is indicated for the twice-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. FP/SAL 250/50 is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations. FP/SAL 250/50 twice daily is the only approved dosage for the treatment of COPD in the US because an efficacy advantage of the higher strength FP/SAL 500/50 over FP/SAL 250/50 has not been demonstrated.
• FP/SAL is NOT indicated for the relief of acute bronchospasm.

Important Safety Information for Advair 250/50 in the US (FP/SAL)

CONTRAINDICATIONS

• FP/SAL is contraindicated for primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required.
• FP/SAL is contraindicated in patients with severe hypersensitivity to milk proteins.

WARNINGS AND PRECAUTIONS

• FP/SAL should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD.
• FP/SAL should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting beta2-agonist, not FP/SAL, should be used to relieve acute symptoms such as shortness of breath.
• FP/SAL should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using FP/SAL should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol, vilanterol) for any reason.
• Oropharyngeal candidiasis has occurred in patients treated with FP/SAL. Advise patients to rinse the mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.

PNEUMONIA WARNING

• There is an increased risk of pneumonia with FP/SAL in patients with COPD.
• Physicians should remain vigilant for the possible development of pneumonia in patients with COPD, as the clinical features of pneumonia and exacerbations frequently overlap.

- In 2 replicate 1-year trials in 1579 subjects with COPD with a history of exacerbations, there was a higher incidence of pneumonia reported in subjects receiving FP/SAL 250/50 (7%) than in those receiving salmeterol 50 mcg (3%). The incidence of pneumonia in subjects treated with FP/SAL 250/50 was higher in subjects over 65 years of age (9%) compared to the incidence in subjects under 65 years of age (4%).

- In a 3-year trial in 6184 subjects with COPD, there was a higher incidence of pneumonia reported in subjects receiving FP/SAL 500/50 compared with placebo (16% receiving FP/SAL 500/50, 14% receiving fluticasone propionate 500 mcg, 11% receiving salmeterol 50 mcg, and 9% receiving placebo). The incidence of pneumonia was higher in subjects over 65 years of age (18% with FP/SAL 500/50 vs 10% with placebo) compared with subjects less than 65 years of age (14% with FP/SAL 500/50 vs 8% with placebo).

WARNINGS AND PRECAUTIONS (cont'd)

• Patients who use corticosteroids are at risk for potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. A more serious or even fatal course of chickenpox or measles may occur in susceptible patients. Use caution in patients with the above because of the potential for worsening of these infections.
• Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. Slowly taper the dose of systemic corticosteroids if transferring patients to FP/SAL.
• Hypercorticism and adrenal suppression may occur with high doses of inhaled corticosteroids, including fluticasone propionate, or at the recommended dose in susceptible individuals. If such effects occur, discontinue FP/SAL slowly.
• The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with FP/SAL is not recommended because increased systemic corticosteroid and increased cardiovascular adverse effects may occur.
• If paradoxical bronchospasm occurs, discontinue FP/SAL immediately and institute alternative therapy.
• Salmeterol, a component of FP/SAL, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. If such effects occur, FP/SAL may need to be discontinued. FP/SAL should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.
• Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating FP/SAL and periodically thereafter.
• Inhaled corticosteroids, as well as poorly controlled asthma, may cause a reduction in growth velocity, and the long-term effect on final adult height is unknown. Patients should be maintained on the lowest dose of inhaled corticosteroid that effectively controls their asthma. Monitor growth of pediatric patients.
• Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with asthma and COPD following the long‐term administration of inhaled corticosteroids, including fluticasone propionate, a component of FP/SAL. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.
• Be alert to hypokalemia, hyperglycemia, and systemic eosinophilic conditions, such as Churg-Strauss syndrome.
• Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, ketoacidosis, and in patients who are unusually responsive to sympathomimetic amines.

ADVERSE REACTIONS: FP/SAL 500/50

• A very common adverse reaction (occurring in >1/10 patients) with FP/SAL 500/50 was Headache. Common adverse reactions (occurring in >1/100 to

ADVERSE REACTIONS: FP/SAL 250/50 FOR ASTHMA

• Most common adverse reactions (incidence ≥3%) in subjects with asthma taking FP/SAL 100/50, FP/SAL 250/50, and placebo, respectively, were upper respiratory tract infection (27%, 21%, 14%), pharyngitis (13%, 10%, 6%), upper respiratory inflammation (7%, 6%, 5%), sinusitis (4%, 5%, 4%), hoarseness/dysphonia (5%, 2%,

ADVERSE REACTIONS: FP/SAL 250/50 FOR COPD

• In subjects with COPD associated with chronic bronchitis, the most common adverse reactions (≥3%) reported in a 6-month clinical trial with FP/SAL 250/50 (and placebo) were headaches, 16% (12%); candidiasis mouth/throat, 10% (1%); musculoskeletal pain, 9% (9%); throat irritation, 8% (7%); viral respiratory infections, 6% (3%); hoarseness/dysphonia, 5% (0%); dizziness, 4% (2%); fever, 4% (3%); sinusitis, 3% (3%); malaise and fatigue, 3% (3%); and muscle cramps and spasms, 3% (1%).
• In the two 1-year trials, the most common events that occurred with a frequency of >5% and more frequently in the subjects treated with FP/SAL than with salmeterol were nasopharyngitis, upper respiratory tract infection, nasal congestion, back pain, sinusitis, dizziness, nausea, pneumonia, candidiasis, and dysphonia.

DRUG INTERACTIONS

• The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with FP/SAL is not recommended because increased systemic corticosteroid and increased cardiovascular adverse effects may occur.
• FP/SAL should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of salmeterol, a component of FP/SAL, on the vascular system may be potentiated by these agents.
• Use beta-blockers with caution as they not only block the pulmonary effect of beta‐agonists, such as salmeterol, a component of FP/SAL, but may also produce severe bronchospasm in patients with asthma or COPD.
• Use FP/SAL with caution in patients taking non-potassium-sparing diuretics (such as loop or thiazide diuretics), as electrocardiographic changes and/or hypokalemia associated with non-potassium-sparing diuretics may worsen with coadministration with beta-agonists, such as salmeterol.

USE IN SPECIFIC POPULATIONS

• Fluticasone propionate and salmeterol are predominantly cleared by hepatic metabolism. Impairment of liver function may lead to accumulation of fluticasone propionate and salmeterol in plasma. Therefore, patients with hepatic disease should be closely monitored.
• The effects of corticosteroids in the treatment of COPD are not well defined, and inhaled corticosteroids, when used apart from approved combination products, are not indicated for COPD.

For the EU Summary of Product Characteristics for FP/SAL, please visit http://www.gsk.com/products.html

Full prescribing information, including BOXED WARNING and Medication Guide, is available at us.gsk.com or US Prescribing Information for FP/SAL.

Important Safety Information for FP (Flixotide/Flovent)

Indications for FP

• FP is indicated for the maintenance treatment of asthma as prophylactic therapy in patients aged 4 years and older. It is also indicated for patients requiring oral corticosteroid therapy for asthma. Many of these patients may be able to reduce or eliminate their requirement for oral corticosteroids over time.
• FP is NOT indicated for the relief of acute bronchospasm.

Important Safety Information for FP

CONTRAINDICATIONS

• FP is contraindicated for primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required.
• FP is contraindicated in patients with severe hypersensitivity to milk proteins. FP is contraindicated in patients with hypersensitivity to any of the ingredients of FP.

WARNINGS AND PRECAUTIONS

• Oropharyngeal candidiasis has occurred in patients treated with FP. Advise patients to rinse the mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.
• FP should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting beta2-agonist, not FP, should be used to relieve acute symptoms such as shortness of breath.
• Patients who use corticosteroids are at risk for potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. A more serious or even fatal course of chickenpox or measles may occur in susceptible patients. Use caution in patients with the above because of the potential for worsening of these infections.
• Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. Slowly taper the dose of systemic corticosteroids if transferring patients to FP.
• Hypercorticism and adrenal suppression may occur with high doses of inhaled corticosteroids, including fluticasone propionate, or at the recommended dose in susceptible individuals. If such effects occur, discontinue FP slowly.
• Immediate hypersensitivity reactions may occur after administration of FP. Discontinue FP if such reactions occur.
• Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care.
• Inhaled corticosteroids, as well as poorly controlled asthma, may cause a reduction in growth velocity, and the long-term effect on final adult height is unknown. Patients should be maintained on the lowest dose of inhaled corticosteroid that effectively controls their asthma. Monitor growth of pediatric patients.
• Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with asthma following the long-term administration of inhaled corticosteroids, including FP. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.
• If paradoxical bronchospasm occurs, discontinue FP immediately and institute alternative therapy.
• The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with FP is not recommended because increased systemic corticosteroid adverse effects may occur.
• Be alert to systemic eosinophilic conditions, such as Churg-Strauss syndrome.

ADVERSE REACTIONS

• Most common adverse reactions (incidence >3%) in subjects taking FP 50 mcg twice daily, FP 100 mcg twice daily, FP 250 mcg twice daily, and placebo, respectively, were upper respiratory tract infection (20%, 18%, 21%, 16%), throat irritation (13%, 13%, 3%, 8%), sinusitis/sinus infection (9%, 10%, 6%, 6%), upper respiratory inflammation (5%, 5%, 0%, 3%), rhinitis (4%, 3%, 1%, 2%), oral candidiasis (
• Most common adverse reactions (incidence >3%) in subjects taking FP 88 mcg twice daily, FP 220 mcg twice daily, FP 440 mcg twice daily, and placebo, respectively, were upper respiratory tract infection (18%, 16%, 16%, 14%), throat irritation (8%, 8%, 10%, 5%), upper respiratory inflammation (2%, 5%, 5%, 1%), sinusitis/sinus infection (6%, 7%, 4%, 3%), hoarseness/dysphonia (2%, 3%, 6%,

DRUG INTERACTIONS

• The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with FP is not recommended because increased systemic corticosteroid adverse effects may occur.

USE IN SPECIFIC POPULATIONS

• Fluticasone propionate is predominantly cleared by hepatic metabolism. Impairment of liver function may lead to accumulation of fluticasone propionate in plasma. Therefore, patients with hepatic disease should be closely monitored.

GSK - one of the world's leading research-based pharmaceutical and healthcare companies - is committed to improving the quality of human life by enabling people to do more, feel better and live longer. For further information please visit www.gsk.com.

Cautionary statement regarding forward-looking statements
GSK cautions investors that any forward-looking statements or projections made by GSK, including those made in this announcement, are subject to risks and uncertainties that may cause actual results to differ materially from those projected. Such factors include, but are not limited to, those described under Item 3.