The U.K. has a long history of leading research into respiratory diseases, stemming from the Industrial Revolution and early studies into tuberculosis.

AstraZeneca PLC is banking that its 40 years of experience in the field will allow the Cambridge-based pharmaceutical group to eclipse its U.K. blue-chip rival, GlaxoSmithKline PLC, which recently tilted its focus toward cancer medicines. With twice as many medicines under development in its respiratory franchise as GSK, AstraZeneca is tackling a myriad of diseases from chronic cough and severe asthma to idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease, once commonly known as smoker's cough. GSK, which introduced the first inhaled asthma medicine in 1969, dropped three experimental drugs in October 2018 as part of an overhaul of research and development undertaken by Hal Barron, leaving it with nine assets for asthma, acute lung injury and muscle weakness from COPD.

Scientists are broadening their approach to lung research in a bid to address increasing numbers of people diagnosed with these chronic diseases, attributed to the steep rise in air pollution combined with smoking, allergies and dietary changes linked to westernization. Drawing from outside the traditional approach to lung disease — including small molecules and monoclonal antibodies — AstraZeneca is deploying modified RNA and the cutting edge gene-editing tool CRISPR, among other approaches, in a bid to reach targets that had previously been inaccessible.

"The inhaled medicines stuff really isn't that interesting for these companies anymore — it's all about these severe asthma products, these protein-based drugs," said an analyst who spoke to S&P Global Market Intelligence on condition of anonymity.

Severe asthma

GSK's Luke Miels, who runs the global pharmaceuticals business, agrees. In addition to the recent setbacks in respiratory research, GSK's blockbuster Advair inhaled asthma treatment succumbed to the long-expected loss of patent exclusivity earlier this year. Advair generated sales of £2.42 billion of GSK's £6.92 billion of global revenue in its respiratory franchise in 2018.

"[GSK has] been very successful with conventional [asthma] medication, so bronchodilators — but what they haven't been so successful at is targeting new things, because that's where you need a lot of investment," said Peter Barnes, Margaret Turner-Warwick Professor of Medicine at the National Heart and Lung Institute and consultant physician at London's Royal Brompton Hospital.

Despite a strategy shift toward oncology and immune-based medicine, Miels pledged an ongoing commitment to GSK's respiratory research, notably severe asthma, which accounts for about 10% of the 334 million people diagnosed with asthma worldwide.

"I think that is the future of asthma treatment, it's biologics," said Miels, who used to run AstraZeneca's global product and portfolio strategy before joining GSK in September 2017.

In 2015, GSK won the first approval for Nucala in severe eosinophilic asthma, two years ahead of any rival medicines. The Brentford, London-based pharma group is now seeking to expand the use of the IL-5 monoclonal antibody to nasal polyps and hypereosinophilic syndrome. Miels signaled that GSK is continuing to explore the role of the IL-5 mechanism, which regulates the growth and life cycle of eosinophils, one of several cell types involved in asthma-related airway inflammation.

However, today Nucala faces competition from other biologics targeting severe asthma, including AstraZeneca's Fasenra, Novartis AG's Xolair and Teva Pharmaceutical Industries Ltd.'s Cinqair. Nucala and Fasenra, both of which work on the IL-5 pathway, have failed in studies for COPD — a condition that affects 350 million people across the world and is the third most common cause of death in high-income countries.

Still, AstraZeneca has Symbicort for COPD and asthma, but the inhaled medicine, which was introduced nearly two decades ago, suffered a 10% drop in 2018 sales to $2.56 billion due to pricing pressures in the U.S. market. Symbicort is a combination of an inhaled corticosteroid and a long-acting bronchodilator.

COPD and aging

Maria Belvisi, the head of AstraZeneca's respiratory, inflammation and autoimmunity biotech unit, believes that respiratory disease needs to be looked at in a different way, across a spectrum of diseases, to better understand the aging process and how it accelerates in COPD. A lot of targets cannot be prosecuted with large biologics and small molecules, which have traditionally been the therapies that pharma produced. AstraZeneca's approach, both internally and by partnering with biotechs, has allowed them to build a new modality platform that can address targets that are not druggable through those two methods, she said.

"It's a very difficult problem to solve because it's a very complicated disease, far more complex than asthma," said Barnes, who has published over 1,000 peer-reviewed papers on asthma and COPD and is an advisory chief scientist to AstraZeneca's respiratory research team. "The mechanism that we're particularly interested in is the acceleration of lung aging. ... We think that in the next few years it will be possible to find new drugs that target this underlying aging process.

"This is very important, not only for COPD but for many other age-related diseases like ischemic heart disease, type 2 diabetes, osteoarthritis, Alzheimer's — all of these diseases involve accelerated aging and it seems like it's the same molecular pathways."

Sanofi's Dupixent, a targeted monoclonal antibody recently approved for eczema and severe asthma, which tackles the interleukin disease pathways IL-4 and IL-13 and may be effective in COPD, is likely to intensify the race to address COPD. Analysts believe it could capture half of the severe asthma market.

Tezepelumab: game changer?

Sanofi and GSK are working on interleukin-33, or IL-33, a protein that is believed to play a key role in the type of inflammation that is linked to asthma. AstraZeneca is hoping that tezepelumab could be a game changer in the severe asthma market after U.S. regulators granted it breakthrough-therapy designation, the first AstraZeneca has received in respiratory medicine. The move was based on phase 2 data that analysts view as highly promising given its positive effect on all biomarkers, coupled with lung function, symptom and exacerbation benefits. "Encouragingly, there could be a potential disease-modifying effect," said Jefferies in a note.

Still, with a depleted offering inside their own labs, GSK's Miels is not ruling out acquiring assets in respiratory that might work on multiple pathways.

"If someone came to us with a target and said 'look, this could work in rheumatoid arthritis, it can work in asthma,' we'd be very interested — you tend to say, follow the science. What is interesting and compelling and then you can work out where it could be used next," he said.

"The lung is difficult," said Belvisi, who is also a professor of respiratory pharmacology at Imperial College London. "People think it's easy because it's easy access, but the lung is designed to expel everything you put in — that's the job of the lung, to get rid of irritants. So you have to have a lot of expertise, not just in the biology of targeting, but in pharma development, and AstraZeneca historically has had that."

Syed Fariq Javaid contributed to this article.