Tackling consequences of air pollution with drug R&D 

When South Korean President Moon Jae-in took office in May 2017, one of his first actions was to sign an order implementing necessary measures to tackle the country’s air pollution crisis.

As a result of rapid industrialisation since the 1980s, South Korea has experienced a significant rise in air pollution. Alongside Poland and South Africa, it has the worst air quality in the Organisation for Economic Co-operation and Development (OECD), particularly in terms of particulate matter.

Yale and Columbia Universities’ 2016 environmental performance index, which was compiled with the World Economic Forum, ranks South Korea 173^rd out of 180 countries in terms of air quality.

This rise in air pollution has contributed to respiratory conditions becoming a key part of the disease burden in South Korea. According to research by the US Centers of Disease Control and Prevention, respiratory tract infections were the most common cause of death in South Korea in 2015; they were responsible of 19.5 per 100,000 deaths in the country.

South Korea is not the only country where air pollution is causing a major environmental health problem and an urgent need for solutions to resolve the problem. In fact, India was recently revealed by the Financial Times to be the world’s most polluted country and, chronic obstructive pulmonary disease (COPD) is now India’s second largest cause of death after heart disease.

Additionally, many developed countries continue to record unacceptably high levels of air pollution in major cities. For example, in 2010 London was found to have the worst air pollution in Europe and in the first month of 2018, the city had already reached its legal limit for air pollution for the entire year. According to the Mayor of London’s office, air pollution is responsible for 9,400 premature deaths in the capital.

The World Health Organization (WHO) has estimated that 91% of the world’s population live in places where air quality exceeds guideline limits, and that outdoor air pollution is responsible for 4.2 million premature deaths and also leads to an increase in hospital admissions and emergency room visits.

Although it can affect organs beyond the lungs, such as the heart, the main disease burdens associated with air pollution are chronic respiratory illnesses, such as asthma, COPD and emphysema, and lung cancer.

The major pollutants that increase the number of cases and exacerbate existing cases of respiratory illnesses are particulate matter, ozone, and sulphur dioxide.

Particulate matter exposure comes mainly from household combustion for cooking, heating and lighting, which are amplified in highly populated areas, and it is proven to have an impact on COPD and lung cancer especially.

Ozone is formed by the photochemical reaction of a range of pollutants, including nitrogen oxides, which are emitted from vehicles, solvents and industry. People with asthma are more sensitive to ozone and so the impact the pollutant has on lung function and airway inflammation has a greater effect.

One form of COPD is chronic bronchitis, which, alongside asthma, is aggravated by sulphur dioxide. This pollutant is produced from burning fossil fuels for domestic heating and power generation for vehicles.

The global respiratory market had a market value of $30.9bn in 2016, according to a 2017 report by Research and Markets, and revenue is expected to rise at a compound annual growth rate of 4.23% to a total of $41.3bn in 2023.

The current standard of care for asthma are corticosteroid and bronchodilator inhalers. The two major types of inhalers are preventers, such as fluticasone and beclomethasone, and relievers, for example salbutamol. Other common medicines for asthma are bronchodilator inhalers, leukotriene receptor antagonists, theophylline and steroid tablets.

COPD can also be treated using inhalers; the first line of treatment is short or long-acting bronchodilator inhalers, followed by corticosteroid inhalers. There are a few bronchodilator inhalers that are not licensed for asthma, but are for COPD; for example, combivent respimat and brovana.

Based on sales revenue, five of the top 20 cancer drugs in 2017 – Avastin, Opdivo, Keytruda, Tarceva and Alimta – were indicated for at least one type of lung cancer.

Among other cancers, Merck’s Keytruda (pembrolizumab) is approved for non-small cell lung cancer (NSCLC). Keytruda is an immunotherapy that targets and blocks PD-1 protein on the surface of T-cells, triggering them to find and destroy cancer cells.

Bristol Myers-Squibb’s Opdivo (nivolumab) is approved for NSCLC in both the US and Europe, and in August 2018 it was approved by the US Food and Drugs Administration (FDA) to treat small cell lung cancer (SCLC). Like Keytruda, Opdivo is a monoclonal antibody that is designed to recognise and attach to the PD-1 protein on T-cells.

Since there remains no cure for chronic respiratory illnesses or lung cancer, and the number of cases is rising, the pharmaceutical industry continues to research and develop new treatments and therapeutic approaches for these conditions.

Noteworthy examples include AstraZeneca and Amgen’s tezepelumab, a monoclonal antibody specific for cytokine thymic stromal lymphopoietin (TSLP), which received breakthrough therapy designation from the FDA in September last year.

In a Phase 2b clinical trial, tezepelumab showed superiority over placebo as an add-on therapy for patients struggling to control their asthma using the standard of care. All three doses of the drug caused a reduction in annual asthma exacerbation rate, compared to placebo.

AstraZeneca chief medical officer and executive vice-president of global medicines development Sean Bohen said: “Tezepelumab is exciting because it has the potential to treat a broad population of severe asthma patients, including those ineligible for currently-approved biologic therapies.”

The companies plan to initiate a phase III study to evaluate the drug’s efficacy and safety over 52 weeks in both adult and adolescent patients.

Researchers from the University of British Columbia, Canada, have discovered that lung damage caused by COPD starts before patients begin showing symptoms, suggesting the existing treatment approach, where patients diagnosed with mild COPD are prescribed minimal or no treatment, needs to be altered.

They studied 34 lung specimens, ten from smokers with normal lung function, ten from patients with mild COPD, eight with moderate COPD and six with severe COPD and centrilobular emphysema. In comparison to the control smoker group, the number of terminal bronchioles decreased by 40% in patients with mild COPD, by 43% for moderate COPD, and 45% for severe COPD.

University of Cambridge researchers, funded by Cancer Research UK, found large quantities of the protein BCL11A in lung squamous cell carcinoma (LUSC) cells and that by manipulating the gene responsible for BCL11A the development of LUSC, which is a type of NSCLC, was halted in a mouse model.

They also figured out the signalling pathway BCL11A is involved in, which led to the researchers finding a potential druggable target, called SETD8. The next stage will be to start developing a drug to target SETD8.

Study author Dr Kyren Lazarus said: “How LUSC develops is a bit of puzzle; until now our molecular understanding of this process was limited. Our research has revealed a major piece of this puzzle, which we are now actively trying to make new drugs against.”

Cancer Research UK’s chief scientist Professor Karen Vousden said: “Identifying potentially druggable targets is an early yet crucial stage in the journey towards precision medicine.

“While there is much to be done before this work could be translated into patient benefit, it’s a fundamental step towards that goal and we look forward to seeing how this discovery progresses along the research pipeline.”