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The long and winding road to asthma breakthroughs

Respiratory biologics are booming thanks to scientists who refused to be derailed by early research setbacks

GSK Steve Yancey

GSK’s vice president and medicines development leader Steve Yancey

Patience and persistence are the prime disciplines of drug development, but knowing when to keep the fuse burning or simply walk away takes a confounding blend of science and emotion.

The raw balance sheet imperatives are often the final arbiter but playing a long game, and funding it, does bring rewards as Steve Yancey, GSK’s vice president and medicines development leader, knows so well.

The company’s severe eosinophilic asthma biologic Nucala (mepoluzimab), an Interleukin-5 inhibitor, has been buoyed by a real-world evidence study – presented at the recent European Respiratory Society’s International Congress in Madrid – which reported a 69% reduction in the annual rate of clinically significant exacerbations.

Nucala, which has the market boost of being licensed for home administration via self- administered auto-injector and prefilled syringe, is running smoothly with approval for the rare disease EGPA in several countries. GSK is also anticipating data in hyper-eosinophilic syndrome and nasal polyposis which could lead to commercial approvals in both by the end of 2020.

Its sales-ringing performance chimes with GSK R&D chief Hal Baron’s strategy to concentrate on the immune system and genetics – Nucala was cited as a prime example of the company’s reinvigorated approach when it was unveiled last year.

Biologics are exquisite

For Yancey and his development team, the spotlight comes after a long and, at times, dispiriting journey stretching over 20 years. Early research in biologics for respiratory diseases did not fare well, with disappointing clinical trials and a danger that the promise would run out of steam.

“Biologics are exquisite in what they can do,” he said. “But it wasn’t that obvious 20 years ago. We were using the dogma and paradigms of one-size-fits-all and that is where we failed.

The early clinical studies with mepoluzimab were unsuccessful, which was disappointing but there were signals in the data that indicated to both the GSK scientists and the wider scientific community that we were beginning to understand more about subtypes, phenotypes and endotypes, which gave us the encouragement to have a long, backward look at our data.

“We spent a lot of hours reviewing our data and the data the academic community was providing and that allowed us to reassess the medicine and understand that we needed to focus on specific populations such as those with serious eosinophilic inflammation. This was the turning point for the development programme.”

The late nights interrogating the science and unpicking data sets prompted the switch from a drug for the broad asthma community to a therapy targeted at a subtype representing around 10% of the asthma population. Nucala had the springboard and the splashdown target.

If the drug’s birth was slow and difficult, its ascent to maturity has been fast-tracked – keeping pace with the wider biologics discovery field – and full of firsts, according to Yancey.

Gold standard

“The development programme pulled through efficacy and safety but we also blazed some new trails, being the first to use patient-reported outcomes to measure the quality of life in these patients where traditional QALY instruments did not work,” said Yancey, who is based at GSK’s Research Triangle in North Carolina, USA.

“We also developed specific protocols to spare oral corticosteroids for those who use them daily, which has become a gold standard study followed by others.

“We have studied more than 3,000 patients in 21 clinical trials and 60,000 patients have received Nucala since it was licensed.”

Severe eosinophilic asthma (SEA) impacts between 5-10% of the population but they, and other severe asthma subtypes, represent 50% of the cost of asthma care expenditure. A third of them are hospitalised at least once a year, more than half have at least one urgent care episode annually, while 25% may have had at least one near fatal experience.

“These figures make us get out of bed every morning,” Yancey says. “Knowing that I am helping patients in some small way to breathe better and to live every breath makes coming to work pretty easy for me.”

The high unmet need was reinforced by a report issued in October by the European Federation of Allergy and Airways Diseases’ Patients’ Associations (EFA), which revealed there were 30 million children and adults under the age of 45 living with asthma in Europe and approximately 10% of those adults suffer severe and life- threatening symptoms.

It also voiced patient concern that asthma and Chronic Obstructive Pulmonary Disease were not getting enough attention compared to other chronic diseases and that patients should play a larger role in medical research.

“We are slightly on a pedestal in that we were the first to approach eosinophilic inflammation in patients with SEA, which allowed us to have the largest breadth of data – five years of safety data,” Yancey added.

Rapid acceleration

Advances in respiratory biologics have opened the door for a move from daily inhaled steroids to monthly injections, delivering greater relief and reducing the condition burden on everyday life – unsurprisingly, studies have shown that 96% of patients prefer self-dosing at home.

But GSK is not alone in the IL-5 inhibitor arena. AstraZeneca’s Fasenra is making waves with its eight-week dosing schedule and $296m in first-half sales – a 244% increase over the same period in 2018. Respiratory biologics is a bustling market.

“There has been a tremendous amount of progress in target respiratory biologics over the last 20 years, but really it has been in the last ten where we have seen the most rapid acceleration, and this has been driven by an evolution in how we think about asthma,” said Yancey.

“Back in the days of small molecules, we thought about large populations and homogenous conditions but, as we move to think about stratified or targeted medicine, we have also come to move the science forward. We recognise that asthma is really a complex heterogeneous disease and it really consists of a number of sub- types and, depending on your sub-type and your expression of the disease, how you will respond to a medicine will vary. This is really the story about biologics; how to understand to target to get the right medicines to the right patient.”

Yancey is full of positivity and pragmatism as Nucala branches out into new applications and the company extends its collaboration sphere. “I always expect bumps on the road – drug development is an incredibly challenging space. Our aim is to overcome them by finding ways of improving our probability of success.

“Our biggest challenge is to be more efficient in picking the winner and not moving as many products or programmes through progression by having a very early look at how we do that.

“One of the strengths of GSK is that we are keen to target genetic links to the disease and mechanism.”

Danny Buckland is a journalist specialising in the healthcare industry

8th November 2019

Danny Buckland is a journalist specialising in the healthcare industry

8th November 2019

From: Research



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