New Therapeutic Options for COPD Indacaterol and Roflumilast Prepared by: Christine Liew (F0158) Preceptor: Lee Chuey Ee

What is COPD? Chronic Obstructive Pulmonary Disease (COPD) is characterized by progressive, partially reversible airflow obstruction, associated with an enhance chronic inflammatory response in the airways. It is a preventable and treatable respiratory disorder.

Table 1: GOLD Classification of Severity of Airflow Limitation in COPD (Based on Post-Bronchodilator FEV1)

Table 2: Model of Symptom/Risk Evaluation of COPD

Table 3: Classification of COPD Severity based on Spirometric Impairment and Symptoms

Treatment Goal for COPD Preventing disease progression Reduce frequency and severity of exacerbations Reduce patient’s symptoms Improve exercise tolerance Improve lung function and general health Improve quality of life

Therapeutic Options Bronchodilators Inhaled short-acting β2-agonist (SABA) Inhaled short-acting anticholinergics (SAAC) Inhaled long-acting β2-agonist (LABA) Inhaled long-acting anticholinergics (LAAC) Methylxanthines Corticosteroids Phosphodiesterase-4 (PDE4) inhibitors

Table 4: Formulations and Typical Dose of COPD Medications

Table 5: Initial Pharmacologic Management of COPD

Current treatments available in UMMC SABA : Fenoterol and Salbutamol SAAC: Ipratropium LAAC: Tiotropium Inhaled corticosteroid (ICS): Fluticasone, budesonide, beclomethasone Combinations of LABA and ICS: Salmeterol/ fluticasone, formeterol/budesonide Systemic corticosteroid: Prednisolone Methylxanthines: Theophylline

Limitations 1. Tiotropium Restricted usage in the hospital. Only 100 patients approved to receive subsidized treatment. 2. Patients still having multiple exacerbations despite on treatment. Current therapy is insufficient to adequately control COPD.

Introducing the New Therapeutic Options

1. Indacaterol Class: Long-acting β2-agonist (LABA) Mechanism of Action (MOA): Stimulate intracellular adenyl cyclase which is responsible for catalyzing the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (AMP). Increased AMP levels cause relaxation of bronchial smooth muscles.

Clinical Review on the Efficacy of Indacaterol in Patients with COPD This review comprises of four placebo- controlled clinical studies of indacaterol treatment in patients with moderate-to- severe COPD. Details on the studies is shown in the next slide.

Table 6: Details on the Four Studies Reviewed

Patient inclusion criteria: Clinical diagnosis of moderate-to-severe COPD Aged 40 years and above Smoking history of at least 20 packs/year Exclusion criteria: -Had recent chest infection or had been hospitalised for an exacerbation or respiratory infection in the 6 weeks before screening - History of asthma - Patient with clinically significant condition that might compromised their safety eg unstable ischemic heart disease, uncontrolled hypertension, uncontrolled diabetes

Baseline Mean duration of COPD from diagnosis of 7 years Mean smoking history of 40-57 packs per year Mean age of 63-64 years old More males (52-80%) than females Patients are allowed to be on ICS, provided the dose and regimen remain unchanged. Spirometry measurements at baseline showed an FEV1 of 53–56% predicted and FEV1/FVC ratio of 0.51–0.53 (both values assessed within 30 min after inhalation of salbutamol 400 μg). Concomitant cardio- or cerebro-vascular conditions were present in 20% of patients, hypertension in 50%, diabetes mellitus in 10%, and hyperlipidaemia in 35%.

Results Figure 1: Bronchodilator effect (FEV1) of Treament

Figure 2: Effect of Treatment on Breathlessness (assessed using transition dyspnoea index [TDI] )

Figure 3: Effect of Treatment on Use of as- needed Salbutamol

Figure 4: Effect of Treatment on COPD Exacerbation Rate

Summary Indacaterol is an once-daily LABA with a rapid onset of action (within 5 minutes), a peak effect at approximately 3 hours, and a duration of bronchodilation lasting at least 24 hours. One of its attraction is its once-daily dosing as compared to the other twice-daily dosing bronchodilators. It might improve adherence. It provides a level of bronchodilation that is similar to tiotropium but greater than the twice-daily agents, formoterol and salmeterol. Indacaterol has a good safety profile.

Indacaterol is an effective and beneficial maintenance bronchodilator treatment for patients with moderate-to-severe COPD. Indacaterol would be a reasonable first choice for maintenance bronchodilator therapy.

Indacaterol

2. Roflumilast Class: PDE-4 inhibitor Mechanism of Action (MOA): Selectively inhibit PDE-4 enzyme, thus preventing the breakdown of cAMP which plays an important role in regulating inflammatory cell activity. Consequently, result in reduced inflammation.

Clinical Trials Data on Roflumilast There are 4 clinical trials which will be discussed. Details on the trials are shown in the next slide.

Table 5: Summary of Roflumilast Phase II and Phase III Clinical Trials, AURA and HERMES

Table 5: Summary of Roflumilast Phase II and Phase III Clinical Trials, EOS and HELIOS

Summary Roflumilast is the first selective PDE4 inhibitor approved in Europe as an add-on anti- inflammatory therapy in patients with symptomatic severe COPD with frequent exacerbations. From the clinical trial data, it is shown that roflumilast improves lung function and reduces exacerbation rates in COPD compared with placebo. When used as an add-on treatment to concomitant bronchodilator therapy, roflumilast shows significant and sustained improvement in lung funtion as compared to placebo.

Significant adverse effects of PDE4 inhibitors includes nausea, diarrhoe, weight loss and headache. Data should be collected to determine the long-term safety of roflumilast. In conclusion, more studies are needed to solidifies roflumilast place in COPD therapy.

Other important areas for further research includes thorough evaluations of the potential synergies and additive effects of: • roflumilast and ICS therapy • roflumilast versus ICS/theophylline as add-on therapy to long-acting bronchodilators.

Figure 5: COPD Treatment Pathway Indicating Suggested Role of PDE4-inhibitors

Roflumilast

References Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease. UK; 2011. Clinical Practice Guidelines: Management of Chronic Obstructive Pulmonary Disease. Ministry of Health Malaysia. 2nd;2009. Micromedex Paul W Jones, Neil Barnes, Claus Vogelmeier, David Lawrence, Benjamin Kramer. Efficacy of Indacaterol in the Treatment of Patients with COPD. Primary Care Respiratory Journal. UK; 2011. Marcos Ribeiro, Kenneth R Chapman. Comparative Efficacy of Indacaterol in COPD. International Journal of COPD. Canada; 2012. David Price, Alison Chisholm, Dermot Ryan, Alan Crockett, Rupert Jones. The Use of Roflumilast in COPD: a primary care perspective. Primary Care Respiratory Journal. UK; 2010. Sabina Antonela Antoniu. New Therapeutic Options in the Management of COPD – focus on roflumilast. UK; 2011.

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