Commentary

Inhaled Therapies for COPD: Present & Future

By Oliver Picken |
30 September 2021
Exploring advancements in inhalation products with Peter J Barnes.

In April, Peter Barnes held a talk at Formulation and Delivery Online: Europe discussing the future of Inhaled Therapies for COPD. In this article we have picked out and summarized several key points. Peter Barnes has published over 1000 peer-review papers on asthma, COPD and related topics and has edited over 50 books. He is also amongst the top 10 most highly cited researchers in the world. He has been the most highly cited clinical scientist in the UK and the most highly cited respiratory researcher in the world over the last 20 years.  

Peter Barnes - Senior Research Investigator at Imperial College London
Peter Barnes – Senior Research Investigator at Imperial College London

Introduction 

COPD (Chronic obstructive pulmonary disease) is a disease that narrows the lung’s small airways, partially blocking airflow in and out of the lungs. The condition may also cause damage to parts of the lung, mucus blocking the airways, or inflammation and enlargement of the airway lining. It is widespread and is currently the third leading cause of death worldwide. It is not an exaggeration to say that many people view COPD as a major global epidemic, and concerns surround its rising prevalence, particularly in lower-income countries. 

The Challenges of Inhaled Therapies for COPD: Pathology and Air Trapping 

The small airway from a COPD patient is narrowed compared to a healthy person due to the thickening of their airway walls. This is a result of inflammation which leads to fibrosis. In addition, patients can exhibit disrupted alveolar attachments in COPD as a consequence of emphysema. These pathological changes have important functional effects. Typically, the airway is narrow on expiration, but they do not close because the alveolar attachments contain elastin fibres. However, in COPD patients, the airway is already narrowed and disrupted all the other attachments, which means that the airway may close completely on expiration. This traps air in the lung, and you can measure this with increased lung volumes. Additionally, air trapping increases during exercise. This is known as dynamic hyperinflation, leading to shortness of breath on exertion and reduced exercise tolerance, which are the major symptoms of COPD.  

There is currently no way to cure or reverse COPD or significantly reduce its progression, but treatment can reduce symptoms and improve quality of life. Unfortunately, in some people, COPD can continue to worsen even with treatment, eventually having a substantial adverse effect on their quality of life and leading to life-threatening problems. Depending on the severity of the disease when diagnosed, the five-year life expectancy for people with COPD varies between 40%-70%. 

Analysing The Current Market: Are Current Treatments Working? 

Inhalation is a well-established method of drug delivery and is the preferred treatment for respiratory disease areas, including COPD, asthma and Cystic Fibrosis. For decades, Dry Powder Inhalers (DPIs), Metered Dose Inhalers (MDIs) and Nebulizers have been used in the topical treatment of lung and pulmonary conditions; these persist as the major therapeutic areas of inhalation drug delivery. 

Bronchodilators 

Bronchodilators relax airway smooth muscle. This is useful for treating symptoms such as coughing, shortness of breath. Bronchodilators are either short-acting or long-acting. Short-acting bronchodilators are used as short-term relief from sudden, unexpected exacerbations, whereas long-acting are used regularly to help control breathlessness in asthma and COPD.  

Inhaled steroids 

Inhaled corticosteroids can reduce respiratory inflammation and help prevent flare-ups. However, side effects may include bruising, oral infections, and hoarseness. These medications are only helpful for people with frequent exacerbations of COPD. Inhaled steroids have rarer and less dangerous side effects than oral steroids; however, there’s still room for concern as inhaled steroids are taken for an extended time. Chances of more significant side effects go up the longer the patient is on high doses of inhaled steroids. In some patients, inhaled steroids may cause ocular hypertension and possibly accelerate cataracts. We need more research to know how serious this potential risk is. 

Combination inhalers 

Some medications combine bronchodilators and inhaled steroids. LAMA/LABA fixed-dose combinations improve lung function, lung hyperinflation, exercise capability, quality of life.  

The Future of Inhaled Therapies for COPD: A New Era? 

The mainstay of COPD Treatment is inhaled long-acting drugs, but there are new classes of drugs in development, such as phosphodiesterase-4 inhibitors. One example, Roflumilast, a once-daily oral inhibitor available for treating severe COPD, is already available. However, it has unpleasant side effects, including diarrhoea and weight loss, which is not popular with patients. This has led to the development of numerous inhaled phosphodiesterase four inhibitors, but most of these failed on efficacy grounds, although they had no side effects.  

PDE3/4 Inhibitor: Ensifentrine 

A PDE3/4 inhibitor called Ensifentrine is in development. Ensifentrine combines anti-inflammatory and bronchodilator properties into one compound. This has the possibility of being an effective treatment for COPD and other respiratory diseases, including asthma and cystic fibrosis. Inhibition of PDE3 causes a bronchodilator effect in while PDE4 which may have anti-inflammatory effects but is 3000 times less potent as inhibiting PDE4 than PDE3. There is no evidence for any anti-inflammatory effects in COPD patients. 

P13K γ/δ Inhibitors 

P13K Gamma Delta inhibitors are anti-inflammatory in vitro and reverse steroid resistance. They are now being tested, but so far, there are no indications that they have significant clinical efficacy.  

Pan-Jak Inhibitors 

Pan jak inhibitors are theoretically good treatments for COPD because they also have anti-inflammatory effects in vitro. Several of these drugs are now in development for inhalation, but efficacy reports have not yet been completed or published.  

Inhaled Cytokine Inhibitors 

So far, cytokine inhibitors, particularly biologics, have not been shown to be effective in COPD. Inhaled antibodies, therefore, would have no particular benefit. But inhaled anticalins, which inhibit cytokines, may have potential in the future if we can find a key inflammatory cytokine to inhibit in COPD.  

Conclusion 

Inhaled long-acting bronchodilators are the most effective treatments we currently have for COPD, and LAMA/LABA combination inhalers have additive bronchodilator effects. In addition, inhaled steroids reduce exacerbations in patients with higher blood eosinophils; in these patients, triple combination inhalers may be convenient.  

There are several new Inhaled Therapies for COPD in development. But so far, none of these have shown efficacy. In the future, what is needed is to target the inhalation therapy more effectively to peripheral airways and in the future to the lung parenchyma. There are thousands of people working on treatments for COPD, it is one of the most critical ventures in modern healthcare, and work will continue as long as the disease remains a problem.  

Speaker Biographies

Peter Barnes – Senior Research Investigator at Imperial College London

Peter Barnes FRS, FMedSci is a Senior Research Investigator at the National Heart and Lung Institute and Honorary Consultant Physician at Royal Brompton Hospital, London. He qualified at Cambridge and Oxford Universities (first-class honours) and was appointed to his present post in 1987. He has published over 1000 peer-review papers on asthma, COPD and related topics and has edited over 50 books. He is also amongst the top 10 most highly cited researchers in the world. He has been the most highly cited clinical scientist in the UK and the most highly cited respiratory researcher in the world over the last 20 years.

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