New Therapies for Asthma & COPD Dr J. Salamzadeh Pharm.D., PhD in Clinical Pharmacy Shahid Beheshti School of Pharmacy

Parts of the lecture Available current drugs at a glance New therapies CFC inhalers vs. HFA-inhalers Conclusion

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Atrovent ® (Ipratropium bromide)

Spiriva Handihaler® (Tiotropium)

Combivent® Ipratropium Br 20 mcg/puff Salbutamol sulfate 100 mcg/puff

Other currently used drug for asthma & COPD Zafirlukast: F.C. tab. 10, 20 mg Intal®: inhalation cap. 20 mg Xanthines Theophylline Aminophylline

New therapies Alvesco® (ciclesonide) (2006) a prodrug ……………… the active metabolite desisobutyryl-ciclesonide (des-CIC) a corticosteroid preventer high lipophilicity creating a reservoir capable of releasing active metabolite from lung epithelial cells prolonged anti-inflammatory effects once-daily-dosing high protein binding (99%) low oral bioavailability (<1%) Limited systemic side-effects سيكلزونايد (80 و 160 mcg/puff) به شرط تولید در داخل کشور و انجام مطالعه بالینی به ليست دارويي كشور اضافه شده است!

New therapies Spiriva ® (Tiotropium bromide) Spiriva Handihaler ® inhalation powder (cap.) for the long-term, once-daily, maintenance treatment of bronchospasm associated with COPD (2004), and for reducing COPD exacerbations (2009). Spiriva Respimat ® inhalation solution maintenance bronchodilator treatment to relieve symptoms of COPD, once a day, 2 puffs. One cartridge contains 4.0 ml providing 60 puffs (30 medicinal doses).

New therapies Omalizumab (Xolair ®) (2003) a recombinant humanised anti-IgE monoclonal antibody Indication: prophylaxis of allergic asthma not responding to high-dose inhaled corticosteroids + long-acting beta2 agonist, in adults and > 12 yrs. as add-on therapy. 2009 (EMA): as an add-on therapy for severe persistent allergic asthma in children between the ages of 6 and 11 years.

New therapies Indacaterol inhalation cap. Onbrez® Breezhaler (EMA, 2009) Arcapta® Neohaler (FDA, 2011) is an ultra-long-acting beta-adrenoceptor agonist (ultra-LABA). half-life ranging from 45 to 126 hours. Duration of action: >24 hrs. licensed only for the maintenance treatment of COPD. EMA: European Medicines Agency

New therapies Daliresp® , Daxas® (Roflumilast) (2011) is an oral tablet to reduce COPD exacerbations. to be taken once daily. the mechanism of action: acts as a selective, long-acting inhibitor of the enzyme PDE-4: to increase intracellular cAMP in lung and immune cells. anti-inflammatory effect. a major limitation: side effect profile: nausea, headaches, and diarrhea. PDE-4 inhibitors are a potentially important new class of agents for COPD. PDE-4: phosphodiesterase 4

New therapies Tudorza® Pressair® & Eklira® Genuair® (Aclidinium bromide inhalation powder) (2012) is an anticholinergic drug. contains a dry powder formulation. for long-term maintenance treatment of COPD. is administered 400 mcg twice a day.

Specific advantages of Aclidinium bromide long-lasting activity at M3 receptors fast onset of action rapid plasma clearance/hydrolysis (t1/2= 2.4 min. in human plasma) sustained bronchodilation very low and transient systemic side-effects

Aclidinium bromide Not to be confused with Clidinium bromide.

New therapies Breo Ellipta® GSK (2013) fluticasone furoate (100mcg) and vilanterol (25 mcg) (ultra-LABA) an inhalation powder. for the treatment of COPD. used as once a day inhalation.

Joint project by GSK & Amira Pharmaceuticals New therapies Inhibitors of 5-lipoxygenase activating protein (FLAP) inhibiting the synthesis of pro-inflammatory leukotrienes. Indication: Inflammatory disorders e.g. asthma. patent drugs under clinical trials : AM103; AM803 Joint project by GSK & Amira Pharmaceuticals

HFA Inhalers: New Respiratory Drug Delivery Systems

Montreal Convention in 1987 to limit usage of Chloro-fluoro-carbons (CFCs): 1 CFC molecule destroys 100,000 molecule of O3 global phase-out: January 1, 2010 1. Hydro-Fluoro-Alkane (HFA) inhalers 2. Dry Powder Inhalers (DPIs)

CFC inhalers vs. HFA inhalers Do patients will notice any change? may taste different may smell different may feel warmer (no “cold freon effect”) may be lighter Technical differences HFA inhalers have a weaker spray. HFA inhalers require a slower inhale. HFA inhalers must be pumped four times (usually) to prime them. HFA inhalers need to be washed with warm water and air dried once a week.

HFA Inhaler; CFC Inhaler; Softer spray Powerful spray

Conclusion Asthma & COPD are highly complex diseases: numerous inflammatory cells and more than 100 mediators participate in asthma and COPD!!! so it is unlikely that targeting a single receptor, mediator or risk factor will be highly effective. It is difficult to discover novel classes of therapy for asthma & COPD, despite intense effort and investment. None of the currently available treatments for asthma & COPD have long-term effects on airway inflammation or remodeling: are not disease-modifying or curative. Patients with severe asthma share several characteristics of patients with steroid resistant COPD: drugs in discovery for COPD may also be effective in treating severe asthma.

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